Source: FDA, National Drug Code (US) Revision Year: 2021
Bamlanivimab is a recombinant neutralizing human IgG1K monoclonal antibody (mAb) to the spike protein of SARS-CoV-2 and is unmodified in the Fc region. Bamlanivimab binds the spike protein with a dissociation constant KD = 0.071 nM and blocks spike protein attachment to the human ACE2 receptor with an IC50 value of 0.17 nM (0.025 μg/mL).
Etesevimab is a recombinant neutralizing human IgG1K mAb to the spike protein of SARS-CoV-2, with amino acid substitutions in the Fc region (L234A, L235A) to reduce effector function. Etesevimab binds the spike protein with a dissociation constant KD = 6.45 nM and blocks spike protein attachment to the human ACE2 receptor with an IC50 value of 0.32 nM (0.046 μg/mL).
Bamlanivimab and etesevimab bind to different but overlapping epitopes in the receptor binding domain (RBD) of the S-protein. Using both antibodies together is expected to reduce the risk of viral resistance.
A flat exposure-response relationship for efficacy was identified for bamlanivimab and etesevimab administered together within the dose range of 700 mg bamlanivimab and 1,400 mg etesevimab to 2,800 mg bamlanivimab and 2,800 mg etesevimab (4 and 2 times the authorized dose, respectively). This flat exposure-response relationship was assessed using available clinical data and pharmacokinetic/pharmacodynamic modeling [see Clinical Trial Results and Supporting Data for EUA (18.2)].
Pharmacokinetic profiles of bamlanivimab and etesevimab are linear and dose-proportional between 700 mg and 7000 mg following a single IV administration. There were no differences in PK of bamlanivimab between severe/moderate participants who were hospitalized and mild/moderate ambulatory participants. There were no differences in PK of etesevimab between mild/moderate ambulatory participants and healthy participants. There is no change in PK of bamlanivimab or etesevimab administered alone or together suggesting there is no interaction between the two antibodies.
The mean maximum concentration (Cmax) of 700 mg bamlanivimab was 196 μg/mL (90% CI: 102 to 378 μg/mL) following approximately 1 hour 700 mg IV infusion.
The mean maximum concentration (Cmax) of 1400 mg etesevimab is estimated to be 504 μg/mL (90% CI: 262 to 974 μg/mL) following approximately 1 hour IV infusion.
Bamlanivimab mean volume of distribution (V) was 2.87 L and 2.71 L for the central and peripheral compartments, respectively. The between subject variability was 23.2% CV.
Etesevimab mean volume of distribution (V) was 2.38 L and 1.98 L for the central and peripheral compartments, respectively. The between subject variability was 27.8% CV.
Bamlanivimab and etesevimab are expected to be degraded into small peptides and component amino acids via catabolic pathways in the same manner as endogenous IgG antibodies.
Bamlanivimab clearance (CL) was 0.27 L/hr (between subject variability 22.3% CV) and the mean apparent terminal elimination half-life was 17.6 days (between subject variability 15.8% CV). Following a single 700 mg IV dose, bamlanivimab was quantifiable for at least 29 days. The mean concentration was 22 μg/mL (90% CI: 10.7 to 41.6 μg/mL) on Day 29.
Etesevimab clearance (CL) was 0.128 L/hr (between subject variability 33.8% CV) and the mean apparent terminal elimination half-life was 25.1 days (between subject variability 29.2% CV). Following a single 1,400 mg IV dose, etesevimab was quantifiable for at least 29 days. The mean concentration was 111 μg/mL (90% CI: 57.4 to 199 μg/mL) on Day 29.
The PK profiles of bamlanivimab and etesevimab were not affected by age, sex, race, or disease severity based on a population PK analysis. Body weight had no clinically relevant effect on the PK of bamlanivimab or etesevimab in adults with COVID-19 over the body weight range of 41 kg to 173 kg [see Use in Specific Populations (11.4, 11.7)].
The PK of bamlanivimab and etesevimab in pediatric patients have not been evaluated.
Using modeling and simulation, the recommended dosing regimen is expected to result in comparable plasma exposures of bamlanivimab and etesevimab in pediatric patients ages 12 years of age or older who weigh at least 40 kg as observed in adult patients [see Use in Specific Populations (11.3)].
Bamlanivimab and etesevimab are not eliminated intact in the urine. Renal impairment is not expected to impact the PK of bamlanivimab and etesevimab, since mAbs with molecular weight >69 kDa are known not to undergo renal elimination. Similarly, dialysis is not expected to impact the PK of bamlanivimab and etesevimab [see Use in Specific Populations (11.5)].
Based on population PK analysis, there is no significant difference in PK of bamlanivimab or etesevimab in patients with mild hepatic impairment compared to patients with normal hepatic function. Bamlanivimab and etesevimab have not been studied in patients with moderate or severe hepatic impairment [see Use in Specific Populations (11.6)].
Bamlanivimab and etesevimab are not renally excreted or metabolized by cytochrome P450 enzymes; therefore, interactions with concomitant medications that are renally excreted or that are substrates, inducers, or inhibitors of cytochrome P450 enzymes are unlikely.
The cell culture neutralization activity of bamlanivimab and of etesevimab against SARS-CoV-2 was measured in a dose-response model quantifying plaque reduction using cultured Vero E6 cells. Bamlanivimab, etesevimab and a 1:1 (weight/weight) ratio of bamlanivimab and etesevimab together neutralized the USA/WA/1/2020 isolate of SARS-CoV-2 with estimated EC50 values = 0.14 nM (0.02 μg/mL), 0.97 nM (0.14 µg/mL) and 0.14 nM (0.02 μg/mL), respectively.
Bamlanivimab demonstrated antibody-dependent cell-mediated cytotoxicity on reporter Jurkat cells expressing FcγRIIIa following engagement with target cells expressing spike protein. Bamlanivimab did not elicit complement-dependent cytotoxicity activity in cell-based assays.
Etesevimab did not demonstrate detectable antibody-dependent cell-mediated cytotoxicity on Jurkat reporter cells expressing FcγRIIIa. Etesevimab did not elicit complement-dependent cytotoxicity activity in cell-based assays.
The risk that bamlanivimab and etesevimab could mediate viral uptake and replication by immune cells was studied in THP-1 and Raji cell lines and primary human macrophages. In general, experiments with bamlanivimab, with etesevimab, and with bamlanivimab and etesevimab together did not demonstrate productive viral infection in immune cells exposed to SARS-CoV-2 at concentrations of mAb(s) down to at least 100-fold below the respective EC50 value(s).
There is a potential risk of treatment failure due to the development of viral variants that are resistant to both bamlanivimab and etesevimab.
Resistant variants were identified using directed evolution of the spike protein and serial passage in cell culture of SARS-CoV-2 in the presence of bamlanivimab or etesevimab individually. Resistant variants were not identified when bamlanivimab and etesevimab were tested together using the same methodology. Viral variants identified in these studies that had reduced susceptibility to bamlanivimab included spike protein amino acid substitutions E484D/K/Q, F490S, Q493R, and S494P, and variants that had reduced susceptibility to etesevimab included substitutions K417N, D420N, and N460K/S/T. Neutralization assays using SARS-CoV-2, vesicular stomatitis virus-based pseudovirus, or binding assessment if pseudovirus construction was unsuccessful (E484D), confirmed reductions in susceptibility to the selecting antibody. Retention of susceptibility to the other antibody alone was observed, with the exception of the Q493R substitution. All variants maintained susceptibility to bamlanivimab and etesevimab together, with the exception of those with E484K, E484Q, and Q493R substitutions, which had reduced susceptibility of 15-fold, 22-fold, and >100-fold, respectively in a pseudovirus assay.
Evaluation of susceptibility of variants identified through global surveillance in subjects treated with bamlanivimab and etesevimab is ongoing. Pseudoviral evaluation of amino acid substitutions identified in global surveillance showed that the V483A substitution reduced susceptibility to bamlanivimab 48-fold, but activity was maintained with etesevimab, and with bamlanivimab and etesevimab together. N501Y and N501T substitutions reduced susceptibility to etesevimab approximately 5-fold and 20-fold, respectively. Activity against variants with N501Y or N501T substitutions was maintained with bamlanivimab alone, and with bamlanivimab and etesevimab together. Pseudovirus harboring spike substitutions K417N + E484K + N501Y together had reduced susceptibility to bamlanivimab or etesevimab alone of >60-fold and >23-fold, respectively, indicating that bamlanivimab and etesevimab together are likely to have reduced activity against viral variants harboring these concurrent substitutions, such as those from B.1.351 (South African origin). Studies are in process to test the activity of bamlanivimab and etesevimab together against additional pseudoviruses and viral variants from this lineage and the related P.1 (Brazilian origin) lineage. Bamlanivimab alone and bamlanivimab and etesevimab together retained activity against pseudovirus expressing del69-70 + N501Y found in the B.1.1.7 variant (UK origin).
Genotypic and phenotypic testing are ongoing to monitor for potential bamlanivimab- and etesevimab-resistance associated spike variations in clinical trials. Detection of phenotypically confirmed bamlanivimab- or etesevimab-resistant variants in baseline samples were observed at a frequency of 0% (0/14) in the Phase 1 clinical study PYAA and 0.4% (2/523) in clinical study BLAZE-1.
In BLAZE-1, treatment-emergent variants were detected at spike protein amino acid positions K417, D420, N460, E484, F490 and S494, and included K417N, D420N, N460T, E484A/D/G/K/Q/V, F490L/S/V and S494L/P substitutions. Only K417N, D420N, N460T, E484D/K/Q, F490S and S494P have been assessed phenotypically to date. At positions K417, D420, N460, E484, F490 and S494, 9.2% (9/98) and 6.1% (6/98) of participants in the 700 mg bamlanivimab arm harbored such a variant post-baseline at ≥15% and ≥50% allele fractions, respectively. For subjects treated with bamlanivimab and etesevimab, the variant frequencies were 3.9% (4/102) and 0% (0/102) at ≥15% and ≥50% allele fractions, respectively. The majority of the variants were first observed on Day 7 following treatment initiation. Some of the variants were detected in individuals at more than one time point in the 700 mg bamlanivimab arm: 4/9 and 4/6 at ≥15% and ≥50% allele fractions, respectively; however, in the bamlanivimab and etesevimab arm there were no such observations (0/4 at ≥15% allele fraction). When the genotypic analysis was restricted to high-risk participants, the 700 mg bamlanivimab arm showed a 14.0% (6/43) and 9.3% (4/43) variant frequency for the ≥15% and ≥50% allele fractions, respectively, and no variants were detected in the bamlanivimab and etesevimab arm. The clinical relevance of these findings is not known.
It is possible that bamlanivimab and etesevimab resistance-associated variants could have cross-resistance to other mAbs targeting the receptor binding domain of SARS-CoV-2. The clinical impact is not known.
There is a theoretical risk that antibody administration may attenuate the endogenous immune response to SARS-CoV-2 and make patients more susceptible to re-infection.
Carcinogenesis, mutagenesis, and reproductive toxicology studies with bamlanivimab or etesevimab have not been conducted.
In toxicology studies, bamlanivimab and etesevimab had no adverse effects when administered intravenously to rats and monkeys, respectively. Non-adverse increases in neutrophils were observed in rats dosed with bamlanivimab.
In tissue cross reactivity studies using human adult and fetal tissues, no binding of clinical concern was detected for bamlanivimab or etesevimab.
Prophylactic administration of bamlanivimab to female Rhesus macaques (n=3 or 4 per group) resulted in 1 to 4 log10 decreases in viral genomic RNA and viral replication (sub-genomic RNA) in bronchoalveolar lavage samples relative to control animals, but less of an impact on viral RNA in throat and nasal swabs following SARS-CoV-2 inoculation.
Prophylactic or therapeutic administration of etesevimab to male Rhesus macaques (n=3 per group) resulted in approximately 4 or 3 log10 average decreases, respectively, in viral genomic RNA in oropharyngeal swabs at Day 4 post infection relative to control animals.
The applicability of these findings to a prophylaxis or treatment setting is not known.
The data supporting this EUA are based on analyses of data from the Phase ⅔ BLAZE-1 trial (NCT04427501) and the Phase 2 BLAZE-4 trial (NCT04634409). Both trials are evaluating the safety and efficacy of bamlanivimab and etesevimab together for treatment of subjects with mild to moderate COVID-19. BLAZE-1 provides clinical efficacy data from subjects receiving 2,800 mg bamlanivimab and 2,800 mg of etesevimab together. BLAZE-4 provides comparative virologic outcome data from subjects receiving 700 mg bamlanivimab and 1,400 mg etesevimab (the authorized doses), subjects receiving 2,800 mg bamlanivimab and 2,800 mg of etesevimab, and placebo.
BLAZE-1 is an ongoing randomized, double-blind, placebo-controlled clinical trial studying bamlanivimab and etesevimab administered together for the treatment of subjects with mild to moderate COVID-19 (subjects with COVID-19 symptoms who are not hospitalized). BLAZE-1 enrolled adult subjects who were not hospitalized and had at least 1 or more COVID-19 symptoms that were at least mild in severity. Treatment was initiated within 3 days of obtaining the clinical sample for the first positive SARS-CoV-2 viral infection determination.
In the Phase 2 portion of the trial, subjects were treated with a single infusion of bamlanivimab 2,800 mg and etesevimab 2,800 mg (N=112), bamlanivimab alone (at doses of 700 mg [N=101], 2,800 mg [N=107], or 7,000 mg [N=101]) or placebo (N=156). The data are from an interim analysis after all enrolled subjects completed at least Day 29 of the trial.
At baseline, median age was 45 years (with 12% of subjects aged 65 or older); 55% of subjects were female, 89% were White, 43% were Hispanic or Latino, and 6% were Black or African American; 42% of subjects were considered high risk (as defined in Section 2). Subjects had mild (78%) to moderate COVID-19 (22%); the mean duration of symptoms was 5 days; mean viral load by cycle threshold (CT) was 24 at baseline. The baseline demographics and disease characteristics were well balanced across treatment groups.
The pre-specified primary endpoint in this Phase 2 trial was change in viral load from baseline to Day 11 for 2,800 mg bamlanivimab and 2,800 mg etesevimab-treated subjects versus placebo. Most subjects, including those receiving placebo, effectively cleared virus by Day 11 (Figure 1).
Figure 1. SARS-CoV-2 Viral Load Change from Baseline by Visit from the Phase 2 Portion of BLAZE-1:
While viral load was used to define the primary endpoint in this Phase 2 trial, the most important evidence that bamlanivimab and etesevimab may be effective came from the predefined secondary endpoint of COVID-19-related hospitalizations or emergency room visits within 28 days after treatment. A lower proportion of bamlanivimab and etesevimab-treated subjects progressed to COVID-19-related hospitalization or emergency room visits compared to placebo-treated subjects (Table 3). No deaths occurred in any treatment arm.
Table 3. Proportion of Subjects with Events of Hospitalization or Emergency Room Visits within 28 Days After Treatment:
| Treatment | Na | Events | Proportion of Subjects % |
|---|---|---|---|
| Placebo | 156 | 9 | 6% |
| Bamlanivimab and etesevimabb | 112 | 1 | 1% |
| Bamlanivimabc 700 mg | 101 | 1 | 1% |
a N = number of treated patients in analysis.
b The doses for bamlanivimab and etesevimab were bamlanivimab 2,800 mg and etesevimab 2,800 mg.
c Results for other doses of bamlanivimab were suggestive of a flat dose-response relationship for this endpoint.
The absolute risk reduction for bamlanivimab and etesevimab-treated subjects compared to placebo is greater in subjects at higher risk of hospitalization according to the high risk criteria (Table 4).
Table 4. Proportion of Subjects with Events of Hospitalization or Emergency Room Visits for Subjects at Higher Risk of Hospitalization:
| Treatment | Na | Events | Proportion of Subjects % |
|---|---|---|---|
| Placebo | 68 | 7 | 10% |
| Bamlanivimab and etesevimab b | 38 | 1 | 3% |
| Bamlanivimab c 700 mg | 46 | 1 | 2% |
a N = number of treated patients in analysis.
b The doses for bamlanivimab and etesevimab were bamlanivimab 2,800 mg and etesevimab 2,800 mg.
c Results for other doses of bamlanivimab were suggestive of a flat dose-response relationship for this endpoint.
The median time to symptom improvement as recorded in a trial specific daily symptom diary was 6 days for bamlanivimab and etesevimab-treated subjects, as compared with 8 days for placebo-treated subjects. Symptoms assessed were cough, shortness of breath, feeling feverish, fatigue, body aches and pains, sore throat, chills, and headache. Symptom improvement was defined as symptoms scored as moderate or severe at baseline being scored as mild or absent, and symptoms scored as mild or absent at baseline being scored as absent.
In the Phase 3 portion of the trial, subjects were treated with a single infusion of bamlanivimab 2,800 mg and etesevimab 2,800 mg (N=518) or placebo (N=517). All of the patients enrolled in these dose arms met the criteria for high-risk (as defined in Section 2).
At baseline, median age was 56 years (with 31% of subjects aged 65 or older); 52% of subjects were female, 87% were White, 29% were Hispanic or Latino, and 8% were Black or African American. Subjects had mild (77%) to moderate (23%) COVID-19; the mean duration of symptoms was 4 days; mean viral load by cycle threshold (CT) was 24 at baseline. The baseline demographics and disease characteristics were well balanced across treatment groups.
The primary endpoint was the proportion of subjects with COVID-19 related hospitalization (defined as ≥24 hours of acute care) or death by any cause by Day 29. Events occurred in 36 subjects treated with placebo (7%) as compared to 11 events in subjects treated with bamlanivimab 2,800 mg and etesevimab 2,800 mg together (2%) [p<0.001], a 70% reduction. There were 10 deaths in subjects treated with placebo and no deaths in subjects treated with bamlanivimab 2,800 mg and etesevimab 2,800 mg together (p<0.001).
At Day 7, 29% of subjects treated with placebo and 10% of subjects treated with bamlanivimab 2,800 mg and etesevimab 2,800 mg together had persistently high viral loads (p<0.000001), which was defined as SARS-CoV-2 viral load >5.27.
Secondary endpoints include mean change in viral load from baseline to Day 3, 5, and 7 (Figure 2).
Figure 2. SARS-CoV-2 Viral Load Change from Baseline by Visit from the Phase 3 Portion of BLAZE-1:
BLAZE-4 is an ongoing Phase 2, randomized, double-blind, placebo-controlled clinical trial studying bamlanivimab and etesevimab for the treatment of subjects with mild to moderate COVID-19 (subjects with COVID-19 symptoms who are not hospitalized). BLAZE-4 enrolled adult subjects who were not hospitalized and had at least 1 or more COVID-19 symptoms that were at least mild in severity, and excluded subjects ≥65 years old or with BMI ≥35. Treatment was initiated within 3 days of obtaining the clinical sample for the first positive SARS-CoV-2 viral infection determination. Subjects were treated with a single infusion of bamlanivimab 700 mg and etesevimab 1,400 mg (N=158), bamlanivimab 2,800 mg and etesevimab 2,800 mg (N=101), bamlanivimab alone at a dose of 700 mg (N=103), or placebo (N=153). Results are not yet complete for additional arms in this trial.
At baseline, median age was 39 years (with 1% of subjects aged 65 or older); 50% of subjects were female, 87% were White, 29% were Hispanic or Latino, and 6% were Black or African American; 8% of subjects were considered high risk (as defined in Section 2). Subjects had mild (84%) to moderate (16%) COVID-19; the mean duration of symptoms was 4 days; mean viral load by cycle threshold (CT) was 25 at baseline. The baseline demographics and disease characteristics were well balanced across treatment groups.
The pre-specified primary endpoint in this Phase 2 trial was the proportion of participants with SARS-CoV-2 viral load greater than 5.27 on Day 7 (+2 days). The rates were 31% (42/135) for placebo, 14% (21/147, p<0.001 versus placebo) for bamlanivimab 700 mg and etesevimab 1,400 mg together, and 10% (10/99, p<0.001 versus placebo) for bamlanivimab 2,800 mg and etesevimab 2,800 mg together.
Secondary endpoints include mean change in viral load from baseline to Day 3, 5, and 7 (Figure 3).
Figure 3. SARS-CoV-2 Viral Load Change from Baseline by Visit from Phase 2 Trial BLAZE-4:
© All content on this website, including data entry, data processing, decision support tools, "RxReasoner" logo and graphics, is the intellectual property of RxReasoner and is protected by copyright laws. Unauthorized reproduction or distribution of any part of this content without explicit written permission from RxReasoner is strictly prohibited. Any third-party content used on this site is acknowledged and utilized under fair use principles.
