Zemaira (Alpha1-Proteinase Inhibitor)

What is Zemaira, and how does it work?

Zemaira is an alpha1-proteinase inhibitor (A1-PI)
indicated for chronic augmentation and maintenance therapy in adults with A1-PI
deficiency and clinical evidence of emphysema.

Zemaira increases antigenic and functional
(anti-neutrophil elastase capacity [ANEC]) serum levels and lung epithelial
lining fluid (ELF) levels of A1-PI.

Clinical data demonstrating the long-term effects of
chronic augmentation therapy of individuals with Zemaira are not available.

The effect of augmentation therapy with Zemaira or any A1-PI
product on pulmonary exacerbations and on the progression of emphysema in A1-PI
deficiency has not been demonstrated in randomized, controlled clinical
studies.

Zemaira is not indicated as therapy for lung disease
patients in whom severe A1-PI deficiency has not been established.

What are the side effects of Zemaira?

The most common adverse reactions (ARs) occurring in at
least 5% of subjects receiving Zemaira in all pre-licensure clinical trials
were

Serious adverse reactions reported following administration of
Zemaira in pre-licensure clinical trials included one event each in separate
subjects of bronchitis and
dyspnea, and one event each in a single subject of
chest pain, cerebral ischemia and
convulsion.

In post-licensure trials, the exposure adjusted incidence
rate (EAIR) of serious exacerbations of chronic obstructive pulmonary disease
(COPD) among subjects was higher during the RAPID Extension trial as compared
to the rate observed during the preceding RAPID trial [see Clinical Trials Experience below].

Serious adverse reactions identified during postmarketing use were
hypersensitivity reactions.

Clinical Trials Experience

Because clinical trials are conducted under widely
varying conditions, adverse reaction rates observed in the clinical trials of a
drug product cannot be directly compared to rates in the clinical trials of
another drug and may not reflect the rates observed in clinical practice.

The following clinical trials were conducted with
Zemaira:

Controlled, double-blind trial in 44 subjects, who received
a weekly 60 mg/kg body weight dose of either Zemaira (30 subjects) or
Prolastin® (a commercially available Alpha1-Proteinase Inhibitor [Human]
product) (14 subjects) for 10 weeks, followed by an open-label phase in which
43 subjects received Zemaira weekly for 14 weeks;
Open-label trial in 9 subjects who received a weekly 60
mg/kg body weight dose of Zemaira for 26 weeks, followed by a 7-week to 22-week
extension;
Crossover, double-blind trial in 18 subjects who received
a single 60 mg/kg dose of Zemaira and a single 60 mg/kg dose of Prolastin;
Open-label trial of 19 subjects who received a single 15
mg/kg (2 subjects), 30 mg/kg (5 subjects), 60 mg/kg (6 subjects), or 120 mg/kg
(6 subjects) dose of Zemaira; and Post-Licensure Randomized, Placebo-Controlled Trial of
Augmentation Therapy in Alpha-1 Protease Inhibitor Deficiency (RAPID), in 180
subjects who received a weekly 60 mg/kg body weight dose of either Zemaira (93
subjects) or placebo (87 subjects) for 24 months (referred to as years 1 and 2
in Table 3).
Post-Licensure Open-label extension of the RAPID trial
involving 140 subjects who had completed blinded treatment with Zemaira or
placebo for 24 months in the RAPID trial and who entered the extension trial
and received open-label Zemaira for up to an additional 24 months (referred to
as years 3 and 4 in Table 3).

Table 1 summarizes the ARs, expressed as events per
subject-year, and the corresponding number of ARs per infusion, expressed as %
of all infusions, for each treatment in prelicensure clinical trials of
Zemaira.

Table 1: Overall Adverse Reactions (ARs) and Serious
ARs

Number of Subjects* (Events per Sub-ject-Year†)
Number of Infusions‡ (% of all Infusions)

Zemaira
(n=66, SY§=28.72)
Prolastin
(n=32), SY§=3.83)
Zemaira
(n=1296)
Prolastin
(n=160)

ARs (AEs assessed by
investigator as at least
possibly related or occurring
during or within
72 hours after the end of
the infusion or for which
causality assessment was
missing or indeterminate).
54 (5.6)
16 (3.8)
160 (12.3)
31 (19.4)

Serious ARs (Serious AEs assessed by investigator as at least possibly related or occurring during or within 72 hours after the end of the infusion or for which causality assessment was missing or indeterminate).
4 (0.2)
1 (1.0)
6 (0.5)
1 (0.6)

* Based on unique subjects. If a subject experienced more
than one AR, the subject was only counted once.
† The exposure adjusted event rate was based on total exposure time presented
in subject-years and the total number of adverse reactions in the database.
‡ If there were multiple occurrences of ARs following a single infusion, only
one occurrence was counted.
§ SY=subject-year.

Table 2 summarizes the ARs occurring in 5% or more
( > 3) subjects, expressed as events per subject-year, and the corresponding
number of ARs per infusion, expressed as % of all infusions, for each treatment
in clinical trials of Zemaira.

Table 2: Adverse Reactions Occurring in ≥ 5% of
Subjects

ARs (AEs assessed by investigator as at least possibly related or occurring during or within 72 hours after the end of the infusion or for which causality assessment was missing or indeterminate).
Number of Subjects* (Events per Sub-ject-Year†)
Number of Infusions‡ (% of all Infusions)

Zemaira
(n=66, SY§=28.72)
Prolastin
(n=32, SY§=3.83)
Zemaira
(n=1296)
Prolastin
(n=160)

Headache
13 (0.7)
5 (1.3)
19 (1.5)
5 (3.1)

Sinusitis
10 (0.5)
1 (0.3)
13 (1.0)
1 (0.6)

Upper Respiratory Infection
10 (0.4)
1 (0.3)
10 (0.8)
1 (0.6)

Bronchitis
5 (0.2)
0 (0.0)
6 (0.5)
0 (0.0)

Asthenia
5 (0.2)
2 (0.5)
5 (0.4)
2 (1.3)

Cough Increased
5 (0.2)
1 (0.5)
5 (0.4)
2 (1.3)

Fever
4 (0.1)
0 (0.0)
4 (0.3)
0 (0.0)

Injection Site Hemorrhage
4 (0.1)
0 (0.0)
4 (0.3)
0 (0.0)

Rhinitis
4 (0.1)
0 (0.0)
4 (0.3)
0 (0.0)

Sore Throat
4 (0.1)
0 (0.0)
4 (0.3)
0 (0.0)

Vasodilation
4 (0.1)
1 (0.3)
4 (0.3)
1 (0.6)

* Based on unique subjects. If a subject experienced more
than one AR of the same type, the subject was only counted once.
†The exposure adjusted event rate was based on total exposure time presented in
subject-years and the total number of adverse reactions in the database.
‡ If more than one of the same type of an event occurred after an infusion,
only one event was counted.
§ SY=subject-year.

Diffuse interstitial lung disease was noted on a routine
chest x-ray of one subject at Week 24. Causality could not be determined.

Chronic Obstructive Pulmonary Disease (COPD)
Exacerbations

In a retrospective analysis, during the 10-week blinded
portion of the 24-week clinical trial, 6 subjects (20%) of the 30 treated with
Zemaira had a total of 7 exacerbations of their chronic obstructive pulmonary
disease (COPD).
Nine subjects (64%) of the 14 treated with Prolastin had a
total of 11 exacerbations of their COPD. The observed difference between groups
was 44% (95% confidence interval [CI] from 8% to 70%).
Over the entire 24-week treatment
period, of the 30 subjects in the Zemaira treatment group, 7 subjects (23%) had
a total of 11 exacerbations of their COPD.
In the 24-week double-blind trial, Zemaira-treated
subjects were tested for
HAV,
HBV, HCV,
HIV, and
parvovirus B19 (B19V), and no
evidence of virus transmission was observed.
In the RAPID study 25 serious
exacerbations of COPD were reported in 15 Zemaira subjects vs. 17 such events in
9 placebo subjects, corresponding to rates of 0.146 exacerbations per subject-year
with Zemaira and 0.115 exacerbations per subject-year with placebo, (ratio Zemaira:Placebo
[95% confidence interval]: 1.256 [0.457 – 3.454]).
Subjects who were randomized to Zemaira in the 2-year
RAPID trial who then entered and received open-label Zemaira in the 2 year
RAPID extension trial were in the “Early Start” group. Subjects who were
randomized to Placebo in the 2-year RAPID trial who then entered and received
open-label Zemaira in the 2 year RAPID extension trial were in the “Delayed
Start” group.
During the RAPID Extension trial 37 serious exacerbations of COPD
were reported in 19 subjects (25%) in the Early Start group, corresponding to
rates of 0.25 exacerbations per subject-year.
In comparison, 20 serious
exacerbations were reported in 11 subjects (17%) in the Delayed Start group
corresponding to rates of 0.16 exacerbations per subject-year (ratio Early:
Delayed [95% confidence interval]: 1.58 [0.68 – 3.66], Table 3).
Among the
Early Start subjects who entered the RAPID extension trial (N = 76), the exposure
adjusted incidence rate of serious exacerbations during the RAPID extension
trial (years 3-4) was 0.25 compared to 0.12 for those subjects during the
earlier RAPID trial(years 1-2), (ratio RAPID Extension:RAPID: 2.10 [95%
confidence interval: 1.21 – 3.67]).
Among the Delayed Start subjects who
entered the RAPID extension trial (N = 64), the exposure adjusted incidence
rate of serious exacerbations during the RAPID extension trial (years 3-4) was
0.16 compared to 0.10 for those subjects during the earlier RAPID trial (years
1-2), (ratio RAPID Extension:RAPID: 1.56 [95% confidence interval: 0.80 –
3.03]).

Table 3: Comparison of Exposure-Adjusted Incidence
Rates for Serious COPD Exacerbations Occurring in the RAPID study between
Zemaira and Placebo subjects and in the RAPID Extension Studies between Early
Start and Delayed Start subjects

Serious COPD Exacer- bations*
Episode
n
%
EAIR (95% CI)
Episode
n
%
EAIR 95% CI
Treatment Ratio for EIAR (95% CI)*

RAPID Study (Years 1 – 2)
Zemaira (N = 93)
Placebo (N = 87)
Zemaira: Placebo

25
15
16.1
0.15 (0.10 -0.22)
17
9
10.3
0.12 (0.07 -0.18)
1.26 (0.46 -3.45)

Extension Study (Years 3 – 4)
Early Start† (N = 76)
Delayed Start‡ (N = 64)
Early: Delayed

37
19
25.0
0.25 (0.18 -0.35)
20
11
17.2
0.16 (0.10 -0.25)
1.58 (0.68 -3.66)

N = total number of safety subjects, n = number of
subjects within a category, % = (n/N)*100, CI = Confidence Interval. Subject
time at risk: Zemaira = 171.14 years, Placebo = 147.75 years, Early Start Group
= 146.46 years, Delay Start Group = 124.71 years.
EAIR = Exposure-Adjusted Incidence Rate (events/subject time at risk). The
point estimates and confidence intervals for
EAIR values were calculated using negative binomial models.
*Episode = Serious exacerbations of COPD identified by investigators as meeting
the Anthonisen criteria¹ plus Serious Adverse Event (SAE) terms
COPD, Condition Aggravated, Bronchitis, Lower Respiratory Tract Infection,
Pneumonia. Serious exacerbation events that overlap or occur within 1 day of
one another were counted as single exacerbation episodes.
†Early Start Group subjects were randomized to Zemaira during the double-blind
RAPID trial (years 1-2) and received open-label Zemaira during the RAPID
extension trial (years 3-4).
‡Delayed Start Group subjects were randomized to Placebo during the
double-blind RAPID trial (years 1-2) and received open-label Zemaira during the
RAPID extension trial (years 3-4).

Immunogenicity

As with all therapeutic proteins, there is potential for
immunogenicity. No anti-A1PI antibodies have been detected in clinical trials
of Zemaira. The detection of antibody formation is highly dependent on the
sensitivity and specificity of the assay.
Additionally, the observed incidence
of antibody (including neutralizing antibody) positivity in an assay may be
influenced by several factors including assay methodology, sample handling,
timing of sample collection, concomitant medications, and underlying disease.
For these reasons, comparison of the incidence of antibodies to Zemaira with
the incidence of antibodies to other products may be misleading.

Postmarketing Experience

Because postmarketing reporting of adverse reactions
is voluntary and from a population of uncertain size, it is not always possible
to reliably estimate the frequency of these reactions or establish a causal
relationship to product exposure.

Table 4 lists the ARs that have been identified during
postmarketing use of Zemaira. This list does not include reactions already
reported in clinical trials with Zemaira [see Clinical Trials Experience above].

Table 4: ARs Reported During the Postmarketing Use of
Zemaira

System Organ Class
Preferred Term/Symptoms

Blood and lymphatic system disorders
Lymph node pain

Gastrointestinal disorders
Nausea

General disorders and administration site conditions
Chills, infusion site reactions, facial, periorbital, lip and extremity swelling, chest pain

Immune system disorders
Hypersensitivity, anaphylactic reactions, tachycardia, hypotension, confusion, syncope, oxygen consumption decreased, pharyngeal edema

Nervous system disorders
Hypoesthesia, paresthesia, dizziness

Skin disorders
Hyperhidrosis, pruritus, rash including exfoliative and generalized, urticaria

Vascular disorders
Flushing

What is the dosage for Zemaira?

For Intravenous Use After Reconstitution Only.

The recommended dose of Zemaira is 60 mg/kg body weight
administered once weekly. Dose ranging studies using efficacy endpoints have
not been performed with Zemaira or any A1-PI product.

What drugs interact with Zemaira?

No information provided.

Is Zemaira safe to use while pregnant or breastfeeding?

Safety and effectiveness in pregnancy have not been established. Zemaira should be given to a pregnant woman only if clearly needed.
It is not known whether Zemaira is excreted in human milk. Use Zemaira only if clearly needed when treating nursing women.

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