Bamlanivimab (Page 10 of 12)

16 NONCLINICAL TOXICOLOGY

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.

17 ANIMAL PHARMACOLOGIC AND EFFICACY DATA

Antiviral Activity In Vivo

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.

18 CLINICAL TRIAL RESULTS AND SUPPORTING DATA FOR EUA

18.1 Treatment of Mild to Moderate COVID-19 (BLAZE-1)

Adults (≥18 Years) and Pediatric Patients (12 to <18 Years Weighing at Least 40 kg)

The data supporting this EUA for treatment of mild to moderate COVID-19 are primarily based on analyses of data from the Phase 2/3 BLAZE-1 trial (NCT04427501). This trial provides Phase 3 placebo-controlled clinical efficacy data from subjects receiving 700 mg bamlanivimab and 1,400 mg of etesevimab together, as well as for subjects receiving 2,800 mg bamlanivimab and 2,800 mg etesevimab together.

BLAZE-1 is a 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. Subjects in the Phase 3 portion of the trial met the criteria for high-risk (as defined in Section 2).

Phase 3 Data from BLAZE-1 (bamlanivimab 700 mg and etesevimab 1,400 mg)

In this portion of the trial, subjects were treated with a single infusion of bamlanivimab 700 mg and etesevimab 1,400 mg (N=511) or placebo (N=258). The majority (99.2%) of the patients enrolled in these dose arms met the criteria for high-risk adults (≥18 years of age) that included at least one of the following: age ≥65 years, BMI ≥35, chronic kidney disease, diabetes, immunosuppressive disease, immunosuppressant treatment, or age ≥55 years with cardiovascular disease, hypertension, chronic pulmonary disease or other chronic respiratory disease. Participants ages 12-17 were also enrolled in the trial (10 [2.0%] were treated with bamlanivimab and etesevimab and 13 [1.7%] were treated with placebo), and met high-risk criteria as defined in the trial protocol.

At baseline, median age was 56 years (with 30% of subjects aged 65 or older); 53% of subjects were female, 87% were White, 27% were Hispanic or Latino, and 8% were Black or African American. Subjects had mild (76%) to moderate (24%) COVID-19; the mean duration of symptoms was 4 days; mean viral load by cycle threshold (CT) was 24.33 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 15 subjects treated with placebo (6%) as compared to 4 events in subjects treated with bamlanivimab 700 mg and etesevimab 1,400 mg together (0.8%) [p<0.0001], an 87% reduction. There were 4 deaths in subjects treated with placebo and no deaths in subjects treated with bamlanivimab 700 mg and etesevimab 1,400 mg together (p=0.01).

Secondary endpoints include mean change in viral load from baseline to Day 3, 5, and 7 (Figure 1).

Figure 1
(click image for full-size original)

Figure 1: SARS-CoV-2 Viral Load Change from Baseline (Mean ± SE) by Visit from the Phase 3 Portion of BLAZE-1 (700 mg bamlanivimab and 1,400 mg etesevimab).

The median time to sustained symptom resolution as recorded in a trial specific daily symptom diary was 8 days for subjects treated with bamlanivimab 700 mg and etesevimab 1,400 mg together as compared with 10 days for subjects treated with placebo (p=0.009). Symptoms assessed were cough, shortness of breath, feeling feverish, fatigue, body aches and pains, sore throat, chills, and headache. Sustained symptom resolution was defined as absence of any of these symptoms, except for allowance of mild fatigue and cough, in two consecutive assessments.

Phase 3 Data from BLAZE-1 (bamlanivimab 2,800 mg and etesevimab 2,800 mg)

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 adults (≥18 years of age) that included at least one of the following: age ≥65 years of age, BMI ≥35, chronic kidney disease, diabetes, immunosuppressive disease, immunosuppressant treatment, or age ≥55 years with cardiovascular disease, hypertension, chronic pulmonary disease or other chronic respiratory disease. Participants ages 12-17 years were also enrolled in the trial (4 [0.8%] were treated with bamlanivimab and etesevimab and 7 [1.4%] were treated with placebo), and met high-risk criteria as defined in the trial protocol.

Bamlanivimab 2,800 mg and etesevimab 2,800 mg is not an authorized dosage under this EUA. 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).

Pediatric Patients <18 Years

The safety and efficacy of bamlanivimab and etesevimab together was evaluated in a total of 125 pediatric subjects enrolled in the Phase 2/3 BLAZE-1 trial (NCT04427501), in which subjects were treated for mild to moderate COVID-19. Pediatric subjects were not hospitalized, and treatment was initiated within 3 days of obtaining the clinical sample for the first positive SARS-CoV-2 viral infection determination. All pediatric subjects met the criteria for high-risk (as defined in Section 2). Pediatric patients weighing 40 kg or more received the same dose as adults (700 mg bamlanivimab and 1,400 mg etesevimab). Pediatric subjects weighing less than 40 kg received weight-based dosing.

Of the 125 pediatric subjects, 33 subjects ages 12 to <18 were evaluated in double-blind, placebo-controlled Phase 3 cohorts of BLAZE-1, and 1 subject age 12 to <18 was evaluated in a controlled addendum to BLAZE-1. Of the 33 pediatric subjects, 14 received placebo, 14 received the authorized dose or a higher dose for their age, and 5 received a lower dose than authorized for their age. A total of 91 pediatric subjects were evaluated in an open-label addendum to BLAZE-1, with 40 subjects ages 12 to <18, 36 ages 6 to <12, 10 ages 2 to <6, and 5 ages 0 to <2. The youngest participant in the trial was 10 months of age and weighed 8.6 kg.

At baseline, median age was 12 years; 46% of subjects were female, 38% were White, 20% were Hispanic or Latino, and 57% were Black or African American. Subjects had mild (88%) to moderate (12%) COVID-19; the mean duration of symptoms was 4 days; mean viral load by cycle threshold (CT) was 5.92 at baseline.

No pediatric subjects died or required hospitalization due to COVID-19. The change in viral load to Day 7 by dose was: -4.23 for subjects treated with 700 mg bamlanivimab and 1,400 mg etesevimab (n=9) and -4.23 for subjects receiving weight-based dosing with bamlanivimab and etesevimab (n=75).

The median time to complete symptom resolution as recorded in a trial specific daily symptom diary was 7 days for subjects treated with bamlanivimab 700 mg and etesevimab 1,400 mg (n=10) and 5 days for subjects treated with weight-based dosing of bamlanivimab and etesevimab (n=91). Symptoms assessed were shortness of breath, nasal congestion, fever, chills, sore throat, stomachache, nausea, vomiting, diarrhea, cough, tiredness, muscle or body aches, headache, new loss of smell, new loss of taste, and poor appetite or poor feeding. Complete symptom resolution was defined as absence of all symptoms at a single timepoint.

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