CLINICAL DATA

EVUSHELD is authorized only for the duration of the declaration that circumstances exist justifying the authorization of the emergency use of EVUSHELD under section 564(b)(1) of the Act, 21 U.S.C. § 360bbb-3(b)(1), unless the authorization is terminated or revoked sooner.

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 of SARS-CoV-2 symptomatic illness (COVID-19).

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.

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.

PROVENT BASELINE CHARACTERISTICS

The baseline demographics were balanced across the EVUSHELD and placebo arms.

PROVENT Baseline Characteristics
PROVENT Baseline Characteristics

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%).

PROVENT EFFICACY DATA

PROVENT (EVUSHELD [150 mg of tixagevimab and 150 mg of cilgavimab])

INCIDENCE OF SYMPTOMATIC COVID-19 IN ADULTS

PROVENT Efficacy Data
PROVENT Efficacy Data

N = number of subjects in analysis; CI = confidence Interval.

*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).

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. 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 vs 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 vs 22/1,731, respectively) with relative risk reduction of 77% (95% CI: 52, 89; p-value <0.001).

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, tachypnea 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. These results are consistent with the duration of protection predicted by population PK modeling. Among subjects who received EVUSHELD there were no severe/critical COVID-19 events compared to five events among subjects who received placebo.

STORM CHASER EFFICACY DATA

STORM CHASER (EVUSHELD [150 mg of tixagevimab and 150 mg of cilgavimab])

STORM CHASER enrolled adults ≥18 years of age following potential exposure (within 8 days) to an identified individual with a laboratory-confirmed SARS-CoV-2 infection (symptomatic or asymptomatic). Subjects could not have previously received a COVID-19 vaccine, have symptoms consistent with COVID-19, or have a known prior SARS-CoV-2 infection. Subjects received a single dose of EVUSHELD (N=749) or placebo (N=372).

The STORM CHASER clinical study in post-exposure patients did not demonstrate benefit for EVUSHELD in preventing symptomatic COVID-19. EVUSHELD is not authorized for post-exposure prophylaxis of COVID-19 in individuals who have been exposed to someone infected with SARS-CoV-2.

ADVERSE REACTIONS FROM CLINICAL STUDIES

Approximately 4,220 subjects have been exposed to EVUSHELD (150 mg of tixagevimab and 150 mg of cilgavimab) in two ongoing Phase III trials, PROVENT and STORM CHASER, for the prophylaxis of COVID-19. Four hundred and fifty two (452) non-hospitalized subjects (with the exception of those hospitalized for isolation purposes) with mild to moderate COVID-19 have been exposed to EVUSHELD (300 mg of tixagevimab and 300 mg of cilgavimab) in one ongoing Phase III clinical trial, TACKLE.

The following adverse events have been observed in the clinical studies of EVUSHELD that supported the EUA. The adverse event rates observed in these clinical studies cannot be directly compared to rates in the clinical studies of other products and may not reflect the rates observed in clinical practice. Additional adverse events associated with EVUSHELD may become apparent with more widespread use.

PROVENT (EVUSHELD [150 mg of tixagevimab and 150 mg of cilgavimab])

In the Phase III PROVENT trial, adverse events were reported in 1,221 (35%) subjects receiving EVUSHELD and 593 (34%) receiving placebo. Serious adverse events were reported in 50 (1%) subjects receiving EVUSHELD and 23 (1%) receiving placebo.

There was 1 adverse event reported as anaphylaxis among subjects who received EVUSHELD. The event began within minutes of EVUSHELD administration and was treated with epinephrine. The event resolved.

Of all reported adverse events (N=4,507), the majority were mild (73%) or moderate (24%) in severity. All adverse events, occurring in at least 1% of subjects, were reported at similar incidence rates among subjects receiving EVUSHELD compared to those receiving placebo (difference <1%). The most common treatment-emergent adverse events, occurring in at least 3% of subjects receiving EVUSHELD or placebo were: headache (6% versus 5%), fatigue (4% versus 3%) and cough (3% versus 3%) EVUSHELD versus placebo, respectively.

At the additional data cut-off (median follow-up 6.5 months), the overall adverse event profile of subjects who received EVUSHELD remained similar to participants who received placebo.

Through the additional data cut-off in PROVENT, a higher proportion of subjects who received EVUSHELD versus placebo in PROVENT reported myocardial infarction SAEs, one of which resulted in death, and cardiac failure SAEs. All subjects who experienced cardiac SAEs had cardiac risk factors and/or a prior history of cardiovascular disease at baseline. There was no clear temporal pattern, which events reported from several hours after EVUSHELD receipt through the end of the follow-up period.

Adverse Reactions from Clinical Studies
Adverse Reactions from Clinical Studies

*One EVUSHELD recipient and one placebo recipient had two cardiac SAEs each.

Includes the preferred terms angina pectoris, coronary artery disease, arteriosclerosis, troponin increased, acute myocardial infarction, and myocardial infarction.

Includes the preferred terms acute myocardial infarction, myocardial infarction, and troponin increased (with a discharge diagnosis of myocardial infarction).

§Includes the preferred terms cardiac failure congestive, acute left ventricular failure, cardiac failure, and cardiac failure acute.

Includes the preferred terms atrial fibrillation, arrhythmia, paroxysmal atrioventricular block, and heart rate irregular.

STORM CHASER (EVUSHELD [150 mg of tixagevimab and 150 mg of cilgavimab])

In the Phase III STORM CHASER trial, adverse events were reported in 162 (22%) subjects receiving EVUSHELD and 111 (30%) receiving placebo. Serious adverse events were reported in 5 (<1%) subjects receiving EVUSHELD and 3 (<1%) receiving placebo. Of the reported adverse events (N=777), the majority of adverse events were mild (75%) or moderate (23%) in severity.

At the additional data cut-off (median follow-up approximately 6 months), the overall adverse event profile for subjects who received EVUSHELD remained similar to earlier results. EVUSHELD is not authorized for post-exposure prophylaxis of COVID-19 in individuals who have been exposed to someone infected with SARS-CoV-2.

In STORM CHASER (N=1,121) no cardiac SAEs were reported (median follow-up approximately 6 months). Compared to PROVENT, the subjects in STORM CHASER were younger (median age 48 versus 57 years) and had fewer baseline cardiac risk factors (24% versus 36% with hypertension, 11% versus 14% with diabetes and 3% versus 8% with cardiovascular disease in STORM CHASER versus PROVENT, respectively).

TACKLE (EVUSHELD [300 mg tixagevimab and 300 mg cilgavimab])

TACKLE enrolled adults ≥18 years of age with mild to moderate COVID-19 who were within ≤7 days of symptom onset. Approximately 90% of study subjects had risk factors that put them at high risk for progression to severe COVID-19. Subjects received a single dose of EVUSHELD (N=452) or placebo (N=451).

In TACKLE, adverse events were reported in 132 (29%) subjects receiving EVUSHELD and 163 (36%) receiving placebo. Serious adverse events were reported in 33 (7%) subjects receiving EVUSHELD and 54 (12%) receiving placebo. Of the reported adverse events (N=520), the majority were mild (56%) or moderate (27%) in severity. There were no reports of anaphylaxis or serious hypersensitivity reactions.

Adverse events of insomnia (1% vs <1%) and dizziness (1% vs none) were reported at a higher rate with EVUSHELD compared to placebo. No other treatment-emergent adverse events, occurring in at least 1% of subjects, were reported at higher incidence rates (difference ≥1%) among subjects receiving EVUSHELD compared to those receiving placebo.

In TACKLE (N=903), four subjects reported cardiac SAEs. Acute myocardial infarction was reported for two subjects who received EVUSHELD (one of whom also experienced cardiac failure leading to death) and sudden cardiac death was reported for one subject who received EVUSHELD. One subject who received placebo reported arrhythmia. All subjects who experienced cardiac SAEs had cardiac risk factors and/or a prior history of cardiovascular disease at baseline.

 

IMPORTANT SAFETY INFORMATION