Vaccine Information: EVUSHELD (Page 5 of 7)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity, genotoxicity, and reproductive toxicology studies have not been conducted with tixagevimab and cilgavimab.

13.2 Animal Toxicology and Pharmacology

In a toxicology study in cynomolgus monkeys, tixagevimab and cilgavimab had no adverse effects when administered via IM injection.

In tissue cross-reactivity studies with tixagevimab and cilgavimab using human adult and fetal tissues no binding of clinical concern was detected.

Tixagevimab and cilgavimab have been assessed in rhesus macaque and cynomolgus macaque models of SARS-CoV-2 infection. Prophylactic administration of tixagevimab and cilgavimab (N= 4 rhesus macaque; N= 3 cynomolgus macaque) three days prior to infection prevented SARS-CoV-2 infection of the upper and lower respiratory tracts in dose-dependent manner. Prophylactic administration of 4 mg/kg tixagevimab and cilgavimab resulted in a 7-log10 reduction in viral sub-genomic messenger RNA (sgmRNA) in nasopharyngeal swabs and 5 to 6-log10 reduction in sgmRNA or infectious virus titer in bronchoalveolar lavage samples at Day 2 post-challenge in all animals relative to placebo-treated animals.

Compared to placebo, prophylactic administration of tixagevimab and cilgavimab (N= 3 cynomolgus macaque) reduced lung injury associated with SARS-CoV-2 infection.

The applicability of these findings to a clinical setting is not known.

14 CLINICAL STUDIES

The data supporting this EUA are based on analyses from the Phase III trials PROVENT (NCT04625725) and STORM CHASER (NCT04625972). Both trials are evaluating the safety and efficacy of EVUSHELD (150 mg of tixagevimab and 150 mg of cilgavimab) for the prophylaxis SARS-CoV-2 symptomatic illness (COVID-19).

Efficacy Data from PROVENT

PROVENT is an ongoing Phase III, randomized (2:1), double-blind, placebo-controlled clinical trial studying EVUSHELD for the pre-exposure prophylaxis of COVID-19 in adults ≥18 years of age. All subjects were either ≥60 years of age, had a pre-specified co-morbidity (obesity, congestive heart failure, chronic obstructive pulmonary disease, chronic kidney disease, chronic liver disease, immunocompromised state, or previous history of severe or serious adverse event after receiving any approved vaccine), or were at increased risk of SARS-CoV-2 infection due to their living situation or occupation. Subjects could not have previously received a COVID-19 vaccine. Subjects received a single dose (administered as two IM injections) of EVUSHELD or placebo. The study excluded subjects with a history of laboratory-confirmed SARS-CoV-2 infection or SARS-CoV-2 antibody positivity at screening. Once COVID-19 vaccines were locally available, subjects were permitted on request to unblind to make an informed decision on vaccine timing and to receive COVID-19 vaccination.

The baseline demographics were balanced across the EVUSHELD and placebo arms. The median age was 57 years (with 43% of subjects aged 60 years or older), 46% of subjects were female, 73% were White, 3% were Asian 17% were Black/African American, and 15% were Hispanic/Latino. Of the 5,197 subjects, 78% had baseline co-morbidities or characteristics associated with an increased risk for severe COVID-19, including obesity (42%), diabetes (14%), cardiovascular disease (8%), cancer, including a history of cancer (7%), chronic obstructive pulmonary disease (5%), chronic kidney disease (5%), chronic liver disease (5%), immunosuppressive medications (3%) and immunosuppressive disease (<1%).

For the primary endpoint, a subject was defined as a COVID-19 case if their first case of SARS-CoV-2 RT-PCR-positive symptomatic illness occurred after administration and prior to Day 183. The primary analysis included 5,172 subjects who were SARS-CoV-2 RT-PCR-negative at baseline, of which 3,441 received EVUSHELD and 1,731 received placebo. Only events that occurred prior to unblinding or vaccine receipt were included. EVUSHELD receipt resulted in a statistically significant (p-value <0.001) 77% reduction in incidence of SARS-CoV-2 RT-PCR-positive symptomatic illness (COVID-19) when compared to placebo (Table 6). At the time of analysis the median follow-up time post-administration was 83 days (range 3 to 166 days).

Similar results were observed for EVUSHELD recipients compared to placebo recipients in the reduction in incidence of SARS-CoV-2 RT-PCR-positive symptomatic illness or death from any cause (12/3,441 versus 19/1,731, respectively) with relative risk reduction of 69% (95% CI: 36, 85; p-value= 0.002), and in the reduction in incidence of SARS-CoV-2 RT-PCR-positive symptomatic illness regardless of unblinding or vaccine receipt (10/3,441 versus 22/1,731, respectively) with relative risk reduction of 77% (95% CI: 52, 89 ; p-value <0.001).

Table 6 Incidence of Symptomatic COVID-19 in Adults (PROVENT)
*
subjects were censored after receiving the vaccine or being unblinded to consider the vaccine, whichever occurred earlier
EVUSHELD dose (150 mg tixagevimab and 150 mg cilgavimab)

N *

Number of events, n (%)

Relative Risk Reduction, % (95% CI)

EVUSHELD

3,441

8 (0.2%)

77% (46, 90)

Placebo

1,731

17 (1.0%)

N = number of subjects in analysis; CI = Confidence Interval

Among subjects who received EVUSHELD, there were no severe/critical COVID-19 events (defined as SARS-CoV-2 RT-PCR-positive symptomatic illness characterized by a minimum of either pneumonia [fever, cough, tachypnoea or dyspnea, and lung infiltrates] or hypoxemia [SpO2 <90% in room air and/or severe respiratory distress] and a WHO Clinical Progression Scale score of 5 or higher) compared to one event (0.1%) among subjects who received placebo.

An additional data cut was conducted to provide post-hoc updated efficacy and safety analysis, the median follow-up was 6.5 months for subjects in both EVUSHELD and placebo arms. The relative risk reduction of SARS-CoV-2 RT-PCR-positive symptomatic illness was 83% (95% CI: 66, 91) with 11/3,441 (0.3%) events in the EVUSHELD arm and 31/1,731 (1.8%) events in the placebo arm, see Figure 1. These results are consistent with the duration of protection predicted by population PK modelling [see Clinical Pharmacology (12.3)]. Among subjects who received EVUSHELD there were no severe/critical COVID-19 events compared to five events among subjects who received placebo.

Figure 1 Kaplan Meier: Cumulative Incidence of Symptomatic COVID-19* (PROVENT)

FIGURE_1
(click image for full-size original)

* Subjects who do not experience a primary endpoint event (and had not discontinued) are censored at Day 183. Subjects who were unblinded/vaccinated prior to an event are also censored at the earlier time of unblinding/vaccination.

Efficacy Data from STORM CHASER

STORM CHASER is an ongoing Phase III randomized (2:1), double-blind, placebo-controlled clinical trial of EVUSHELD for the post-exposure prophylaxis of COVID-19 in adults ≥18 years of age. Subjects who had not previously received a COVID-19 vaccine were enrolled following potential exposure (within 8 days) to an identified individual with a laboratory-confirmed SARS-CoV-2 infection (symptomatic or asymptomatic). Subjects received a single dose (administered as two IM injections) of EVUSHELD or placebo. The study excluded subjects with a history of laboratory-confirmed SARS-CoV-2 infection or SARS-CoV-2 antibody positivity at screening. Once COVID-19 vaccines were locally available, subjects were permitted on request to unblind to make an informed decision on vaccine timing and to receive COVID-19 vaccination.

Of the 1,121 subjects who were randomized and received EVUSHELD (N= 749) or placebo (N= 372), 48 subjects were positive for SARS-CoV-2 (RT-PCR analysis of nasopharyngeal swabs) at baseline.

The primary efficacy analysis, comparison of the incidence of a subject’s first case of SARS-CoV-2 RT-PCR-positive symptomatic illness occurring post-dose and before Day 183, did not demonstrate a statistically significant effect for EVUSHELD versus placebo with 23 cases of symptomatic COVID-19 in the EVUSHELD arm (3.1%) and 17 cases in the placebo arm (4.6%) (relative risk reduction of 33%, 95% CI: -26, 65). At the time of analysis the median follow-up time post-administration was 49 days (range 5 to 115 days).

The study did not demonstrate benefit for EVUSHELD in preventing symptomatic COVID-19 in the first 30 days after randomization, leading to the limitation of use for post-exposure prophylaxis [see Emergency Use Authorization (1)]. However, there was a higher proportion of symptomatic COVID-19 cases among placebo recipients after Day 29 (see Figure 2 below, data from the post-hoc updated efficacy analysis with a median follow-up time of 6.5 months). EVUSHELD is not authorized for post-exposure prophylaxis of COVID-19 in individuals who have been exposed to someone infected with SARS-CoV-2.

Figure 2 Kaplan Meier: Cumulative Incidence of Symptomatic COVID-19* (STORM CHASER)

FIGURE_2
(click image for full-size original)

* Subjects who do not experience a primary endpoint event (and had not discontinued) are censored at Day 183.

16 HOW SUPPLIED/STORAGE AND HANDLING

How Supplied

Each EVUSHELD co-packaged carton contains two vials (Table 7):

1 single-dose vial of tixagevimab injection as a sterile, preservative-free, clear to opalescent and colorless to slightly yellow solution.
1 single-dose vial of cilgavimab injection as a sterile, preservative-free, clear to opalescent and colorless to slightly yellow solution.
Table 7 EVUSHELD co-packaged carton contents

Carton

(2 vials per pack)

Components

1 vial of Tixagevimab

150 mg/1.5 mL (100 mg/mL)

(dark grey cap)

1 vial of Cilgavimab

150 mg/1.5 mL (100 mg/mL)

(white cap)

NDC 0310-7442-02

NDC 0310-8895-01

NDC 0310-1061-01

Storage and Handling

Store unopened vials in a refrigerator at 2°C to 8°C (36°F to 46°F) in the original carton to protect from light. Discard any unused portion.

DO NOT FREEZE. DO NOT SHAKE.

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