Zemaira (Alpha1-Proteinase Inhibitor)

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.

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

• headache,
• sinusitis,
• upper respiratory infection,
• bronchitis,
• asthenia,
• cough increased,
• fever,
• injection site hemorrhage,
• rhinitis,
• sore throat, and
• vasodilation.

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

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

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

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

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.

• 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.