Mechanism Of Action
A1-PI deficiency is a chronic, hereditary, autosomal,
co-dominant disorder that is usually fatal in its severe form. Low blood levels
of A1-PI (i.e., below 11 μM) are most commonly associated with
progressive, severe emphysema that becomes clinically apparent by the third to
fourth decade of life. In addition, PiSZ individuals, whose serum A1-PI levels range
from approximately 9 to 23 mM, are considered to have a moderately increased risk
for developing emphysema, regardless of whether their serum A1-PI levels are
above or below 11 mM.2 Not all individuals with severe genetic
variants of A1-PI deficiency have emphysema. Augmentation therapy with Alpha1-Proteinase
Inhibitor (Human) is indicated only in patients with severe congenital A1-PI
deficiency who have clinically evident emphysema. A registry study showed
54% of A1-PI deficient subjects had emphysema.3 Another registry
study showed 72% of A1-PI deficient subjects had pulmonary symptoms.4
Smoking is an important risk factor for the development of emphysema in
patients with A1-PI deficiency.
Approximately 100 genetic variants of A1-PI deficiency
can be identified electrophoretically, only some of which are associated with
the clinical disease.5,6 Ninety-five percent of clinically
symptomatic A1-PI deficient individuals are of the severe PiZZ phenotype. Up to
39% of A1-PI deficient patients may have an asthmatic component to their lung
disease, as evidenced by symptoms and/or bronchial hyperreactivity.3 Pulmonary
infections, including pneumonia and acute bronchitis, are common in A1-PI
deficient patients and contribute significantly to the morbidity of the
Augmenting the levels of functional protease inhibitor by
intravenous infusion is an approach to therapy for patients with A1-PI
deficiency. However, the efficacy of augmentation therapy in affecting the
progression of emphysema has not been demonstrated in randomized, controlled
clinical studies. The intended theoretical goal is to provide protection to the
lower respiratory tract by correcting the imbalance between NE and protease
Whether augmentation therapy with Zemaira or any A1-PI
product actually protects the lower respiratory tract from progressive
emphysematous changes has not been evaluated. Individuals with endogenous
levels of A1-PI below 11 mM, in general, manifest a significantly increased
risk for development of emphysema above the general population background risk.6,7,8,9
Although the maintenance of blood serum levels of A1-PI (antigenically
measured) above 11 mM has been historically postulated to provide
therapeutically relevant antineutrophil elastase protection10, this
has not been proven. Individuals with severe A1-PI deficiency have been shown
to have increased neutrophil and NE concentrations in lung epithelial lining
fluid compared to normal PiMM individuals, and some PiSZ individuals with A1-PI
above 11 mM have emphysema attributed to A1-PI deficiency.2 These
observations underscore the uncertainty regarding the appropriate therapeutic
target serum level of A1- PI during augmentation therapy.
Pulmonary disease, particularly emphysema, is the most
frequent manifestation of A1-PI deficiency.6 The pathogenesis of
emphysema is understood to evolve as described in the “protease-antiprotease
imbalance” model. A1-PI is now understood to be the primary antiprotease in the
lower respiratory tract, where it inhibits NE.11 Normal healthy individuals
produce sufficient A1-PI to control the NE produced by activated neutrophils and
are thus able to prevent inappropriate proteolysis of lung tissue by NE.
Conditions that increase neutrophil accumulation and activation in the lung,
such as respiratory infection and smoking, will in turn increase levels of NE.
However, individuals who are severelydeficient in endogenous A1-PI are unable
to maintain an appropriate antiprotease defense and are thereby subject to more
rapid proteolysis of the alveolar walls leading to chronic lung disease.
Zemaira serves as A1-PI augmentation therapy in this patient population, acting
to increase and maintain serum levels and (ELF) levels of A1-PI.
Weekly repeated infusions of A1-PI at a dose of 60 mg/kg
lead to serum A1-PI levels above the historical target threshold of 11 mM.
The clinical benefit of the increased blood levels of A1-PI
at the recommended dose has not been established for any A1-PI product.
A double-blind, randomized, active-controlled, crossover
pharmacokinetic study was conducted in 13 males and 5 females with A1-PI
deficiency, ranging in age from 36 to 66 years. Nine subjects received a single
60 mg/kg dose of Zemaira followed by Prolastin, and 9 subjects received
Prolastin followed by a single 60 mg/kg dose of Zemaira, with a washout period
of 35 days between doses. A total of 13 post-infusion serum samples were taken
at various time points up to Day 21. Table 6 shows the mean results for the Zemaira
Table 6: Pharmacokinetic Parameters for Antigenic A1-PI
in 18 Subjects Following a Single 60 mg/kg Dose of Zemaira
|Area under the curve (AUC0-∞)
||144 (±27) μM x day
|Maximum concentration (Cmax)
||44.1 (±10.8) μM
|Terminal half-life (t½β)
||5.1 (±2.4) days
||603 (±129) mL/day
|Volume of distribution at steady state
||3.8 (±1.3) L
|* n=18 subjects.
Animal Toxicology And/Or Pharmacology
In a safety pharmacology study, dogs were administered a
60 or 240 mg/kg intravenous dose of Zemaira. At the clinical dose of 60 mg/kg,
no changes in cardiovascular and respiratory parameters or measured hematology,
blood chemistry, or electrolyte parameters were attributed to the
administration of Zemaira. A minor transient decrease in femoral resistance and
increase in blood flow were observed after administration of the 240 mg/ kg
In single-dose studies, mice and rats were administered a
0, 60, 240, or 600 mg/kg intravenous dose of Zemaira and observed twice daily
for 15 days. No signs of toxicity were observed up to 240 mg/kg. Transient
signs of distress were observed in male mice and in male and female rats after
administration of the highest dose (600 mg/kg).
In repeat-dose toxicity studies, rats and rabbits
received 0, 60, or 240 mg/kg intravenous doses of Zemaira once daily for 5
consecutive days. No treatment-related effects on clinical signs, body weight,
hematology, coagulation, or urinalysis were observed in rats administered up to
240 mg/kg. No signs of toxicity were observed in rabbits administered 60 mg/kg.
Changes in organ weights and minimal epidermal ulceration were observed in rabbits
administered 240 mg/kg, but had no clinical effects.
The local tolerance of Zemaira was evaluated in rabbits
following intravenous, perivenous,and intraarterial administration. No
treatment-related local adverse reactions were observed.
Clinical trials were conducted pre-licensure with Zemaira
in 89 subjects (59 males and 30 females). The subjects ranged in age from 29 to
68 years (median age 49 years). Ninety-seven percent of the treated subjects
had the PiZZ phenotype of A1-PI deficiency, and 3% had the MMALTON phenotype.
At screening, serum A1-PI levels were between 3.2 and 10.1 mM (mean of 5.6 mM).
The objectives of the clinical trials were to demonstrate that Zemaira augments
and maintains serum levels of A1-PI above 11 mM (80 mg/dL) and increases A1-PI
levels in ELF of the lower lung.
In a double-blind, controlled clinical trial to evaluate
the safety and efficacy of Zemaira, 44 subjects were randomized to receive 60
mg/kg of either Zemaira or Prolastin once weekly for 10 weeks. After 10 weeks,
subjects in both groups received Zemaira for an additional 14 weeks. Subjects
were followed for a total of 24 weeks to complete the safety evaluation [see
ADVERSE REACTIONS]. The mean trough serum A1-PI levels at steady state (Weeks
7-11) in the Zemaira-treated subjects were statistically equivalent to those in
the Prolastin-treated subjects within a range of ±3 mM. Both groups were
maintained above 11 mM. The mean (range and standard deviation [SD]) of the
steady state trough serum antigenic A1-PI level for Zemaira-treated subjects
was 17.7 mM (range 13.9 to 23.2, SD 2.5) and for Prolastin-treated subjects was
19.1 mM (range 14.7 to 23.1, SD 2.2). The difference between the Zemaira and
the Prolastin groups was not considered clinically significant and may be
related to the higher specific activity of Zemaira.
In a subgroup of subjects enrolled in the trial (10
Zemaira-treated subjects and 5 Prolastintreated subjects), bronchoalveolar
lavage was performed at baseline and at Week 11.Four A1-PI related analytes in
ELF were measured: antigenic A1-PI, A1-PI:NE complexes, free NE, and functional
A1-PI (ANEC). A blinded retrospective analysis, which revised the prospectively
established acceptance criteria showed that within each treatment group, ELF levels
of antigenic A1-PI and A1-PI:NE complexes increased from baseline to Week 11 (Table
7). Free elastase was immeasurably low in all samples. The post-treatment ANEC
values in ELF were not significantly different between the Zemaira-treated and
Prolastin-treated subjects (mean 1725 nM vs. 1418 nM). No conclusions can be
drawn about changes of ANEC values in ELF during the trial period as baseline
values in the Zemaira-treated subjects were unexpectedly high. No A1-PI
analytes showed any clinically significant differences between the Zemaira and
Prolastin treatment groups.
Table 7: Change in ELF From Baseline to Week 11 in a
||Mean Change From Baseline
||822.6 to 1894.0
||460.0 to 1439.7
||-2032.3 to 856.1
||-392.3 to 1387.2
|A1-PI:NE Complexes (nM)
||39.9 to 196.1
||49.8 to 524.5
|CI, confidence interval.
* n=10 subjects.
† n=5 subjects.
The clinical efficacy of Zemaira or any A1-PI product in
influencing the course of pulmonary emphysema or pulmonary exacerbations has
not been demonstrated in adequately powered, randomized, controlled clinical
2. Turino GM, Barker AF, Brantly ML, et al. Clinical
features of individuals with PI*SZ phenotype of α1-antitrypsin deficiency.
Am J Respir Crit Care Med. 1996;154:1718-1725.
3. Stoller JK, Brantly M, et al. Formation and current
results of a patient-organized registry for α1-antitrypsin deficiency. Chest.
4. McElvaney NG, Stoller JK, et al. Baseline characteristics
of enrollees in the National Heart, Lung, and Blood Institute Registry of α1-Antitrypsin
Deficiency. Chest. 1997;111:394-403.
5. Crystal RG. α1-antitrypsin deficiency, emphysema,
and liver disease; genetic basis and strategies for therapy. J Clin Invest.
6. World Health Organization. Alpha-1-antitrypsin
deficiency; Report of a WHO Meeting. Geneva. 18-20 March 1996.
7. Eriksson S. Pulmonary emphysema and alpha1-antitrypsin
deficiency. ACTA Med Scand. 1964;175(2):197-205.
8. Eriksson S. Studies in α1-antitrypsin deficiency.
ACTA Med Scan Suppl. 1965;432:1-85.
9. Gadek JE, Crystal RG. α1-antitrypsin deficiency.
In: Stanbury JB, Wyngaarden JB, Frederickson DS, et al., eds. The Metabolic
Basis of Inherited Disease. 5th ed. New York, NY: McGraw-Hill; 1983:1450-1467.
10. American Thoracic Society. Guidelines for the
approach to the patient with severehereditary alpha-1-antitrypsin deficiency. Am
Rev Respir Dis. 1989;140:1494-1497.
11. Gadek JE, Fells GA, Zimmerman RL, Rennard SI, Crystal
RG. Antielastases of the human alveolar structures; implications for the
protease-antiprotease theory of emphysema. J Clin Invest. 1981;68:889-898.