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(Chest. 2002;122:66-74.)
© 2002 American College of Chest Physicians

Biochemical Efficacy and Safety of a New Pooled Human Plasma {alpha}1-Antitrypsin, Respitin*

James K. Stoller, MS, MD, FCCP; Farshid Rouhani, MS; Mark Brantly, MD; Seta Shahin, MS; Raed A. Dweik, MD, FCCP; James M. Stocks, MD, FCCP; Jack Clausen, MD; Edward Campbell, MD and Frank Norton, PhD

* From the Department of Pulmonary and Critical Care Medicine (Drs. Stoller and Dweik), Cleveland Clinic Foundation, Cleveland, OH; Pulmonary-Critical Care Branch (Mr. Rouhani), National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD; University of Florida College of Medicine (Dr. Brantly), Gainesville, FL; Alpha Therapeutic Corporation (Ms. Shahin and Dr. Norton), Los Angeles, CA; University of Texas Health Center (Dr. Stocks), Tyler, TX; University of California San Diego (Dr. Clausen), San Diego, CA; and University of Utah Health Sciences Center (Dr. Campbell), Salt Lake City, UT.

Correspondence to: James K. Stoller, MS, MD, FCCP, Department of Pulmonary and Critical Care Medicine, A 90, The Cleveland Clinic Foundation, 9500 Euclid Ave, Cleveland, OH 44195; e-mail: stollej{at}ccf.org


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Background: Augmentation therapy with pooled human plasma-derived {alpha}1-antitrypsin (AAT) has been shown to have biochemical efficacy in restoring serum AAT levels above the protective threshold. Also, clinical efficacy has been suggested.

Objective: To evaluate the bioequivalence of a new solvent detergent-treated preparation of pooled human plasma-derived AAT (proposed name Respitin; Alpha Therapeutic Corporation; Los Angeles, CA) to the commercially available preparation (Prolastin; Bayer Corporation; West Haven, CT), we conducted a randomized controlled trial.

Methods: Eligible subjects were adults (> 18 years of age) who had never smoked or were ex-smokers, had severe deficiency of AAT, and had fixed airflow obstruction (ie, postbroncholdilator FEV1 of 30 to 80% of predicted values and/or diffusing capacity of the lung for carbon monoxide [DLCO] of < 70% of predicted values with evidence of emphysema on a CT scan). Of the 28 subjects recruited, 26 completed the 12-week comparison. Participants were randomized to receive Respitin (60 mg/kg once weekly; 14 subjects) or Prolastin (60 mg/kg once weekly; 14 subjects), and recipients of Prolastin then crossed over to receive Respitin thereafter for the 24-week duration of the study.

Results: The primary efficacy criteria were satisfied for equivalence to comparator (ie, the ratio of mean trough serum levels for Respitin/Prolastin at weeks 8 to 11 exceeded the efficacy criterion [0.905; p = 0.0206] as did the slope of the mean trough level over weeks 11 to 23 [-0.003 µmol per week]). In Respitin recipients, the trough serum antineutrophil elastase capacity at week 7 and at weeks 8 to 11 was also equivalent to the comparator, as was the rise in AAT levels in epithelial lining fluid from baseline to week 7. The levels of urinary elastin degradation products showed little appreciable change for > 24 weeks, and no difference between compared groups was shown through week 12. Adverse events were similarly infrequent in compared groups. Finally, neither spirometry measurements nor DLCO showed a significant change through 24 weeks.

Conclusions: We conclude that this new solvent detergent-treated pooled human plasma-derived AAT (Respitin) demonstrates biochemical equivalence to Prolastin and that this new drug is well-tolerated.

Key Words: {alpha}1-antitrypsin deficiency • antiprotease • efficacy • safety


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Augmentation therapy for severe deficiency of {alpha}1-antitrypsin (AAT), which is the IV infusion of purified AAT to raise serum levels above the protective threshold of 80 mg/dL (or 11 µmol),1 first achieved US Food and Drug Administration approval in 1989 with a pasteurized pooled human plasma product (Prolastin; Bayer Corporation; West Haven, CT). Over the last decade, significant advances have been made that have enhanced the current understanding of the biochemical and clinical efficacy of IV augmentation therapy1 2 3 4 5 and that have made available new preparations of pooled human plasma AAT and alternative treatments. For example, the infusion of pasteurized pooled human plasma antiprotease at a weekly dose of 60 mg/kg has been shown to raise serum levels of AAT and to maintain nadir levels above the protective threshold while maintaining serum antineutrophil elastase capacity.1 Similarly, the presence of AAT in the epithelial lining fluid indicates diffusion through the interstitium, again with preservation of antineutrophil elastase capacity.

In addition to evidence of the biochemical efficacy of IV augmentation therapy, at least two large observational cohort studies suggest that IV augmentation therapy has clinical efficacy. Specifically, a comparison of German recipients of augmentation therapy with Danish nonrecipients2 showed that the rate of decline of FEV1 was significantly slowed in treated patients (by 22 mL per year; p < 0.05). More recently, results from the National Heart, Lung, and Blood Institute (NHLBI) Registry of Individuals with {alpha}1-Antitrypsin Deficiency3 have shown that recipients of augmentation therapy experienced enhanced survival (risk ratio, 0.64; p < 0.05) and that the subset of individuals with American Thoracic Society stage II COPD (FEV1, 35 to 49% of predicted) experienced a slower rate of decline of FEV1 than nonrecipients (by 27 mL per year; p < 0.05).

Finally, in a randomized, double-blind, placebo-controlled clinical trial of IV augmentation therapy, Dirksen et al5 reported a trend toward a slower loss of lung density, as seen on chest CT scans, among recipients vs nonrecipients of monthly infusions of {alpha}1-antiprotease therapy.

In the context that IV augmentation therapy appears to have clinical efficacy and that available supplies of pasteurized AAT have been inadequate to supply patients for whom such therapy is indicated, there has been an impetus to develop new treatment alternatives for patients with AAT deficiency. The current research evaluates the biochemical efficacy and safety of a new pooled human plasma AAT preparation, proposed name Respitin (Alpha Therapeutic Corporation; Los Angeles, CA), which has undergone solvent detergent treatment and nanofiltration to enhance viral safety.


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Study Drug
Respitin is a human {alpha}1-proteinase inhibitor. The product is derived from units of pooled human plasma, which have been tested and found to be nonreactive for hepatitis B surface antigen (HBsAg) and hepatitis C (HCV) antibody, and negative for antibodies to HIV-1 and HIV-2. All units of plasma that were used to prepare this drug had alanine aminotransferase levels that were less than twice the upper limit of normal of the expected range for the assay method used. To reduce the potential risk of transmission of infectious agents, the product was treated with an organic solvent/detergent mixture, tri(n-butyl)/phosphate/polysorbate 80, that was designed to inactivate enveloped viruses, such as HIV, hepatitis B, and HCV. Viral removal was further enhanced by the addition of a nanofiltration step. The functional activity of each vial was determined by the ability of Respitin to neutralize porcine pancreatic elastase, and dosing was based on functional Respitin.

Study Design
The design is a randomized, double-blind bioequivalence study with an active control in which subjects were randomly allocated to the study drug Respitin (60 mg/kg once weekly by IV infusion) or the comparator (Prolastin; Bayer Corporation; West Haven, CT; 60 mg/kg once weekly) for 10 weeks, after which all subjects received Respitin at the same dose for a total study duration of up to 2 years.

The primary objective of the study was to evaluate the biochemical efficacy and safety in subjects with severe AAT deficiency. More specifically, the primary hypotheses were the following: (1) Respitin is equivalent (ie, not inferior) to the comparator in mean trough serum AAT levels over weeks 8 to 11; and (2) the trough serum AAT levels between weeks 11 and 24 describe a line the slope of which exceeds -0.1 with 90% confidence. Secondary outcome measures (Table 1 ) were determined in all subjects and included serum antineutrophil elastase capacity at weeks 8 to 11 and measurements of epithelial lining fluid obtained by BAL (which was performed at baseline and after the sixth study drug infusion), including AAT levels, antineutrophil elastase capacity, interleukin (IL)-8 levels, and polymorphonuclear leukocyte counts. Spirometry, chest radiographs, and high-resolution CT scans of the chest were performed serially (Table 1) . Finally, additional outcome measures assessed the magnitude of elastin breakdown and included levels of urinary desmosine (assayed both by the methods of Starcher and Scott6 and Stone and coworkers7 8 ) and isodesmosine.


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  		Table 1. Schedule of Procedures*

 
The assessment of safety was based on ascertaining the number of adverse events (AEs), the measurement of complete blood counts, the results of liver function tests, the presence of AAT antibodies, viral serologic conversion (to hepatitis A, HBsAg, HCV, HIV-1, and HIV-2), and vital signs during drug infusions.

Eligibility criteria included the following: (1) documented severe AAT deficiency with serum levels of < 11 µmol; (2) the presence of airflow obstruction as indicated by a postbronchodilator FEV1 between 30% and 80% of predicted and an FEV1/FVC ratio of < 0.70, or, if FEV1 was > 80% of predicted, a diffusing capacity of the lung for carbon monoxide (DLCO) of < 70% of predicted and CT scan evidence of emphysema; (3) reported abstinence from smoking for at least 6 months; (4) age > 18 years; (5) agreement to practice adequate contraception; and (6) the availability of informed consent.

Exclusion criteria included the following: (1) prior receipt of IV augmentation therapy within 6 months; (2) the use of another investigational drug within 2 months; (3) severe gas exchange abnormality (ie, room air PaO2 <= 55 mm Hg and/or PaCO2 >= 46 mm Hg); (4) baseline seropositivity for HBsAg, HCV, HIV-1, or HIV-2; (5) the presence of an ongoing or recurrent inflammatory lung process (eg, bronchiectasis or interstitial lung disease); (6) elevation of serum transaminase levels within 6 months; (7) renal dysfunction (ie, serum creatinine levels > 1.5 times the upper limit of normal); (8) IgA deficiency; (9) the presence of antibodies to AAT; and (10) pregnancy or nursing state.

Measurement Methods
BAL Protocol:
After adequate sedation and analgesia, bronchoscopy and BAL were performed with the subject in the supine position. The bronchoscope was wedged into the anterior segment of the right or left upper lobe. BAL was performed in each lobe with five sequential 20-mL aliquots of normal saline solution, which were infused quickly with no dwell time between infusion and aspiration. BAL fluid from both lobes was combined, and the percentage of the recovered volume was measured. Mucus was removed from BAL fluid using two layers of sterilized cotton gauze. The total cell count was determined using a hemocytometer. Two slides with 50,000 cells each were made using cytofunnels and centrifugation at 600 revolutions per minute for 10 min. Cells were separated from the BAL fluid at 2,000 revolutions per minute for 15 min. The BAL fluid then was separated and stored at -70°C. The percentage of viable cells was determined by trypan blue exclusion.9

Amount and Function of Human AAT in BAL Fluid and Blood:
Levels of AAT in the epithelial lining fluid that was recovered by BAL were quantified with an enzyme-linked immunoassay1 10 11 and were corrected for the volume of epithelial lining fluid as measured by the urea method.12 Antigenic AAT levels in the serum were measured by nephelometry (Nephelometer Analyzer; Behring Diagnostics; Westwood, MA). Nephelometric measurement of the sample serum was made at a dilution of 1:20 of serum mixed with anti-AAT antisera, and the results were expressed in micromoles per liter.13 The antineutrophil elastase capacity of the BAL fluid and serum was quantified by titrating increasing amounts of the fluid being analyzed against a fixed amount of a titrated standard of purified human neutrophil elastase. After incubation for 5 min at 37°C, elastase activity was measured as absorbance at 405 to 490 nm, using the neutrophil elastase substrate methoxy-succinyl-ala-ala-pro-val-nitroanilide1 (Sigma; St. Louis, MO). AAT phenotypes were determined by the isoelectic focusing of serum in polyacrylamide gels at pH 4.2 to 4.9.14

Measurement of Elastin Degradation:
In the context that urine desmosine, a breakdown product of mature lung elastin,6 7 8 can reflect lung elastin breakdown, urinary levels of desmosine were measured using the following two different methods: a radioimmunoassay technique described by Starcher and Scott6 ; and an isotope dilution technique employing high-performance liquid chromatography, as described by Stone and coworkers.7 8

Statistical Analysis
In this bioequivalence study, power calculations were based on a mean serum AAT level of 14 ± 2 µmol/L observed after > 4 weeks of infusing Prolastin at 60 mg/kg once weekly. Assuming 90% power to detect a difference of 20% between the mean serum levels after the infusion of Respitin vs infusion of the comparator, and {alpha} < 0.05 (two-sided), 24 available subjects were deemed necessary.

The noninferiority of the test to the control drug for the mean serum {alpha}1-antiprotease and antineutrophil elastase capacity trough levels (ie, immediately prior to infusion) at day 7 of week 6 and across weeks 8 through 11 was evaluated using a one-sided 5% level Sasabuchi t test.15 16 Confidence intervals were constructed to test the null hypothesis that the means for the test drug were < 80% of the means for the control drug.

The mean serum {alpha}1-antiprotease levels during weeks 12 through 24 were analyzed by computing a regression slope for each subject employing a first-order, time-series autoregressive model that used all the available data.17 A two-sided 90% confidence interval for the mean slope was computed to demonstrate that the lower limit of the observed slope did not include the value -0.1 µmol/L/wk.

Using a software package (TopFit, version 2.0; Gustav Fischer; New York, NY) and a noncompartmental model, the individual half-life values of the compared drugs were determined during a 7-day period following the first treatment infusion. Confidence intervals were constructed to test the null hypotheses that the means for the test drug were either < 80% or > 125% of the means for the control drug.

For BAL measurements, the mean changes from baseline to week 7 for {alpha}1-protease inhibitor and antineutrophil elastase were computed for each treatment group. Two-sided 90% confidence intervals were calculated for the difference in means for neutrophil count, and for levels of neutrophil elastase complex and free neutrophil elastase.

For each AE, we calculated the percentage of infusions in which an AE occurred, the percentage of subjects who experienced the event, and the cumulative number of AEs for infusions 1 through 23 by treatment arm. AEs were tallied separately for each study drug and for weeks 1 through 10 and weeks 11 through 23.


   Results
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
A total of 28 subjects was recruited into the study (Table 2 ). Of the 14 subjects who were allocated to each drug, one patient withdrew from each group (due to unwillingness to adhere to the protocol in the study drug group and the development of pneumonia after the removal of an incidentally found airway foreign body during the baseline bronchoscopy in the control group), leaving 13 subjects in each study arm who completed the 12-week comparison. Baseline characteristics of the compared groups were similar (Table 2) .


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  		Table 2. Baseline Characteristics of Study Participants*

 
As shown in Figures 1 and 2 , the primary efficacy criteria for equivalence to the comparator were satisfied. Specifically, the ratio of mean trough serum levels (Respitin/comparator) at weeks 8 to 11 was 0.905 (Fig 1) , with the lower 95% confidence interval exceeding the efficacy criterion of 0.80 (p = 0.026). Also, the slope of the mean trough serum levels over weeks 11 to 23 was -0.003 µmol per week with a lower 90% confidence limit of -0.04 (Fig 2) . Because this lower confidence limit exceeded the efficacy criterion of a slope of > -0.1, the null hypothesis was rejected, prompting the conclusion that Respitin was also equivalent with regard to this outcome measure.



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  		Figure 1. Serum {alpha}1-protease inhibitor levels following IV augmentation with 60 mg/kg active Respitin ({diamondsuit}; n = 13) or the control ({blacksquare}; n = 13). The number of weeks of augmentation therapy with either Respitin or control {alpha}1-protease inhibitor is shown on the abscissa.

 


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  		Figure 2. A comparison of serum {alpha}1-protease inhibitor levels following IV augmentation with 60 mg/kg active Respitin ({diamondsuit}; n = 13) or control ({blacktriangleup}; n = 13) during weeks 1 to 11 and with all subjects receiving Respitin ({blacksquare}; n = 26) during weeks 12 to 24. The number of weeks of augmentation therapy either with Respitin or control {alpha}1-protease inhibitor is shown on the abscissa.

 
As summarized in Table 3 , the ratio of Respitin to the comparator (0.996) for the change in trough serum antineutrophil elastase capacity at week 7 (p = 0.01) and for the trough serum antineutrophil elastase capacity at weeks 8 through 11 (0.975; p = 0.003) also supported the conclusion of equivalence, although the ratio of AAT serum levels (Respitin/comparator ratio, 0.842) at week 7 did not (p = 0.301).


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  		Table 3. Summary of Outcomes*

 
BAL was performed at baseline and at week 7 in 5 of 13 Respitin recipients (38.5%) and in 3 of 13 control recipients (23.0%). As shown in Figure 3 , AAT levels in the epithelial lining fluid showed a rising trend in both groups (mean rise in Respitin group, 1,103 ± 905 nmol/L; mean rise in control group, 1,188 ± 432 nmol/L) but was variable between patients. Similarly, the change in levels of AAT-neutrophil elastase complexes in the epithelial lining fluid from baseline to week 7 was similar for Respitin and the control recipients (mean rise, 114 ± 206 vs 136 ± 177 nmol/L, respectively). Although neutrophil elastase activity in the epithelial lining fluid rose slightly in Respitin recipients (21 ± 215 nmol/L) and fell slightly in control recipients (-40 ± 61 nmol/L), the mean antineutrophil elastase capacity in the epithelial lining fluid rose similarly in both groups (mean rise in Respitin recipients, 856 ± 943 nmol/L; mean rise in control recipients, 779 ± 575 nmol/L). Finally, the mean baseline IL-8 levels in the epithelial lining fluid were higher in Respitin recipients (14,316 ± 4,996 ng/mL) than in control recipients (4,111 ± 1,107 ng/mL; p = 0.004), and those levels fell in Respitin recipients (10,304 ± 4,558 ng/mL) but rose slightly in control recipients (1,048 ± 2,619 ng/mL).



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  		Figure 3. Comparison of epithelial lining fluid of {alpha}1-protease inhibitor (ELF A1PI) concentrations prior to (week 1) and following (week 7) 6 weeks of augmentation therapy with either Respitin (white bars) or the control A1PI (black bars). Error bars represent the SEM.

 
Levels of urinary desmosine measured both by the methods of Starcher and Scott6 and Stone and coworkers7 8 showed little appreciable change over the course of 24 weeks (Fig 4 ), and no differences between the Respitin and control recipients over the first 12 weeks of the study were observed. Pharmacokinetic studies over the first week of drug infusion showed a serum half-life of 5.7 days for Respitin (n = 14) and 5.0 days for the comparator (n = 13).



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  		Figure 4. Urinary desmosine concentrations determined by two different methods prior to and during augmentation therapy with Respitin or control {alpha}1-protease inhibitor are shown. Left ordinate: urinary desmosine concentration determined by high-performance liquid chromatography. Right ordinate: urinary desmosine concentrations determined by radioimmunoassay. Values are represented by lines and symbols. {blacktriangleup} = Respitin (n = 13); {blacksquare} = control (n = 13); white columns = Respitin; black columns = control. Error bars represent the SEM. At week 12 and beyond, all subjects received study drug.

 
AEs
The rate of AEs classified as definitely, probably, or possibly related to the study drug did not differ significantly between the treatment and control groups. Specifically, on a per-infusion basis over weeks 1 through 10, 5 of the 14 subjects (who received 136 infusions of Respitin) experienced AEs (3.7%) vs 3 of the 14 subjects (who received 131 infusions of the comparator [2.3%]). Between weeks 11 and 24 (when all subjects crossed over to receive Respitin), an additional five AEs were reported. Evaluated on an "intent-to-treat" basis with AEs ascribed to the initial group allocation, the AE rate was 2.2% per infusion for Respitin recipients (7 of 318 recipients) and 1.9% (6 of 313 recipients) for Prolastin recipients.

The signs and symptoms of AEs over > 24 weeks in the 14 subjects who initially were allocated to receive Respitin (a total of nine episodes in 5 subjects) included rash/itching (two episodes in 2 subjects), headaches (three episodes in 2 subjects), and one episode each of lightheadedness, fever/chills, facial flushing, and visual disturbance characterized by a brief (5-min) inability to focus. In recipients of Prolastin, the 12 signs and symptoms that were experienced included rash/hives (two episodes), fever/chills (one episode), cough (one episode), dyspnea (one episode), chest pain (one episode), drowsiness (four episodes), edema (one episode), and a pulmonary infiltrate (one episode). Using the standard rating criteria applied by the blinded investigators, all signs and symptoms were deemed to be mild, except for three, all of which were allocated to comparator. Specifically, chest pain and dyspnea occurred once each and were considered to be of moderate severity. Also, as indicated above, one patient experienced a pulmonary infiltrate, which was considered to be a severe AE. In this instance, the subject was found to have a foreign body in the bronchus intermedius as an incidental finding during the baseline bronchoscopy. The foreign body proved to be a plastic sandwich "sword," which he subsequently recalled having aspirated 17 years earlier. After eliciting additional consent to remove the foreign body, the patient underwent a second bronchoscopy and later experienced aspiration pneumonia, causing him to withdraw from study participation prior to receiving Prolastin.

Lung Function
As presented in Table 4 , pulmonary function did not change significantly over the 7 weeks of infusions of either Respitin or Prolastin. Similarly, no significant change from baseline was evident in any pulmonary function tests at week 24.


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  		Table 4. Pulmonary Function Tests*

 
Viral Seroconversion
No instance of viral seroconversion (from negative to positive IgG) at 11 or 24 weeks was observed for hepatitis A, hepatitis B, HCV, HIV-1, or HIV-2 in recipients of either Respitin or Prolastin.


   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
The main findings of this study are as follows: (1) a new solvent detergent-prepared, pooled, human plasma-derived {alpha}1-antiprotease called Respitin demonstrated equivalence to Prolastin in achieving trough serum AAT levels above the protective threshold of 11 µmol at weeks 8 to 11; (2) IV augmentation therapy with Respitin (60 mg/kg functionally active {alpha}1-antiprotease once weekly) maintained trough serum levels steadily (ie, with a slope exceeding -0.01 over weeks 11 to 23 of treatment); (3) Respitin was equivalent to Prolastin in maintaining serum antineutrophil elastase capacity at week 7 and at weeks 8 to 11; (4) IV augmentation therapy with Respitin was well-tolerated, with similarly low rates of AEs as Prolastin; (5) lung function tests were similarly unchanged over the initial 7 weeks of therapy with both Respitin and Prolastin, and remained stable through week 24 of receiving Respitin therapy; and (6) recognizing that cautious interpretation is required by the higher baseline levels of IL-8 Prolastin recipients, the diminution of IL-8 levels in the BAL fluid of Respitin recipients is consistent with an anti-inflammatory effect of this new pooled human plasma {alpha}1-antiprotease.

Overall, these results recommend Respitin as an equivalent alternative for IV augmentation therapy of patients with severe AAT deficiency. Another drug feature that might recommend Respitin includes its preparation using independent (and therefore redundant) purification techniques (ie, solvent detergent and nanofiltration) vs pasteurization alone.

Even if Respitin represents no more than an equivalent alternative to Prolastin, the availability of an additional source of {alpha}1-antiprotease for IV augmentation therapy should help to address the needs of AAT-deficient individuals with COPD for whom the drug is not currently available. Specifically, estimates suggest that there are 100,000 PI*Z AAT-deficient individuals in the United States,18 19 of whom approximately 3,000 to 4,000 are currently receiving IV augmentation therapy based on maximal current production capacity. Although the fraction of all PI*Z individuals with COPD remains uncertain, even if only a conservative estimate of 15% were affected, the current maximal production capacity would produce only 27% of the needed supply (ie, 4,000 of 15,000 individuals). Thus, the prospect of a new alternative drug with equivalent efficacy will likely be welcomed by individuals who are currently unable to receive {alpha}1-antiprotease for IV augmentation therapy.

Although the clinical efficacy of IV augmentation therapy has not been definitively shown in a randomized controlled clinical trial to date,2 3 4 5 the following evidence suggests that IV augmentation therapy has efficacy:

  1. The criteria for biochemical efficacy have been satisfied for Prolastin1 and Respitin (ie, that the infusion of both drugs restores serum AAT levels and functional activity to values exceeding protective thresholds).
  2. The results of two observational studies2 3 agree in suggesting that IV augmentation therapy has clinical efficacy to slow the rate of FEV1 decline and, in one study,3 to decrease mortality in AAT-deficient COPD patients. Specifically, in an observational cohort study comparing 198 German subjects with AAT deficiency and COPD who received weekly infusions of Prolastin (60 mg/kg) to 97 Danish subjects who did not receive augmentation therapy, the rate of FEV1 decline was significantly lower in the augmentation recipients (by 22 mL per year; p = 0.02).2 Similarly, in the NHLBI Registry of Individuals with {alpha}1-Antitrypsin Deficiency, the subset analysis showed that individuals with stage II COPD (FEV1, 35 to 49% of predicted) receiving augmentation therapy experienced a slower rate of FEV1 decline (by 27 mL per year; p = 0.03) than did nonrecipients of augmentation therapy.3 Furthermore, in the NHLBI Registry, patients receiving augmentation therapy experienced a lower risk of mortality (risk ratio, 0.64; p = 0.02) than did nonrecipients. Although not based on a randomized controlled clinical trial, these concordant observations suggest that IV augmentation therapy has clinical efficacy and bolsters the recommendation from the American Thoracic Society that augmentation therapy should be considered for patients with COPD due to severe AAT deficiency.20
  3. The results of a randomized, placebo-controlled clinical trial of monthly IV augmentation therapy have shown a trend (p = 0.07) toward a slower rate of loss of lung density on chest CT scans in augmentation therapy recipients.

In summary, the results of the current study suggest that a new pooled human plasma-derived {alpha}1-antiprotease prepared using solvent detergent and nanofiltration methods (Respitin) has equivalent biochemical efficacy to Prolastin. On this basis, this new drug represents a treatment alternative that can help to provide augmentation therapy to patients whose current need cannot be met and to the many affected, but as yet unidentified, individuals with severe AAT deficiency.


   Footnotes
 
Abbreviations: AE = adverse event; AAT = {alpha}1-antitrypsin; DLCO = diffusing capacity of the lung for carbon monoxide; HBsAg = hepatitis B surface antigen; HCV = hepatitis C virus; IL = interleukin; NHLBI = National Heart, Lung, and Blood Institute

This research was funded by the Alpha Therapeutic Corporation. Dr. Stoller’s relationship to Alpha Therapeutic Corporation relates only to having served as the principal investigator in one of the study sites in the described trial. Neither any family member nor he has any ongoing financial or consultative interests in this company or product. He also serves as an investigator or consultant to studies sponsored by other companies developing {alpha}1-antitrypsin deficiency-relevant products, including Bayer, Aventis Behring, and Baxter. Dr. Brantly had a clinical study contract with Alpha Therapeutic Corporation to perform the testing of samples while he was an employee of the National Heart, Lung, and Blood Institute at the National Institutes of Health and of the University of Florida. He does not own stock in Alpha Therapeutic Corporation, nor has he been a paid consultant on the speakers bureau of Alpha Therapeutic Corporation. Dr. Dweik received nothing of value from any commercial party related directly or indirectly to the subject of this article. Dr. Clausen has no financial interests in Alpha Therapeutic Corporation nor in the product that has evolved, other than serving as principal investigator for the University of California San Diego site in this study. Alpha Therapeutic Corporation paid a reasonable and customary fee for Dr. Campbell’s portion of the work involved in the completion of this study. He has no other financial connection with Alpha Therapeutic Corporation. Bayer Corporation currently markets a product that is similar to, and will compete with, Respitin. Dr. Campbell has been a consultant for Bayer Corporation, and Bayer Corporation has provided financial support for a clinical diagnostic laboratory (HerediLab, Inc) for which he serves as Laboratory Director. Otherwise, he has no equity interest in any organization that has a direct financial interest in the broad subject area discussed in the manuscript. Dr. Stock’s only tie to the product Respitin and to Alpha Therapeutic Corporation was as an investigator in the clinical research trial described in this article through his appointment at the University of Texas Health Center. Neither his family members nor he has any ongoing financial or consultative interests in this company or the product in question. Dr. Stock has active research contracts with companies (Aventis Behring and the American Red Cross) that have potential competitors to Respitin in clinical trial. Mr. Rouhani worked with Dr. Brantly at the National Heart, Lung, and Blood Institute at the National Institutes of Health to perform the testing of samples from Alpha Therapeutic Corporation. Furthermore, he neither owns any stock nor has any financial interest in Alpha Therapeutic Corporation. At the time that the work described in the article was performed, Dr. Norton was an employee of the Alpha Therapeutic Corporation. Other than compensation for that position, he received no compensation from any other source for Respitin or any other drug for the treatment of {alpha}1-antitrypsin deficiency. At the time that the work described in this article was performed, Ms. Shahin was an employee of Alpha Therapeutic Corporation. Other than compensation for that position, she received no compensation from any other source for work performed on Respitin or any other drug for the treatment of {alpha}1-antitrypsin deficiency.

Received for publication September 28, 2000. Accepted for publication February 20, 2001.


   References
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

  1. Wewers, MD, Casolaro, MA, Sellers, SE, et al (1987) Replacement therapy for {alpha}1-antitrypsin deficiency associated with emphysema. N Engl J Med 316,1055-1062[Abstract]
  2. Seersholm, N, Wencker, M, Banik, N, et al (1997) Does alpha 1-antitrypsin augmentation therapy slow the annual decline in FEV1 in patients with severe hereditary {alpha}1-antitrypsin deficiency? The Wissenschaftliche Arbeitsgemeinschaft zur Therapie von Lungenerkrankungen (WATL) {alpha}1-AT Study Group. Eur Respir J 10,2260-2263[Abstract]
  3. . The Alpha 1-Antitrypsin Deficiency Registry Study Group. (1998) Survival and FEV1 decline in individuals with severe deficiency of {alpha}1-antitrypsin. Am J Respir Crit Care Med 158,49-59[Abstract/Free Full Text]
  4. Wencker, M, Banik, N, Buhl, R, et al (1998) Long-term treatment of {alpha}1-antitrypsin deficiency-related pulmonary emphysema with human {alpha}1-antitrypsin. Eur Respir J 11,428-433[Abstract]
  5. Dirksen, A, Dijkman, JH, Madsen, F, et al (1999) A randomized clinical trial of {alpha}1-antitrypsin augmentation therapy. Am J Respir Crit Care Med 160,1468-1472[Abstract/Free Full Text]
  6. Starcher, B, Scott, M (1992) Fractionation of urine to allow desmosine analysis by radioimmunoassay. Ann Clin Biochem 29,72-78
  7. Stone, PJ, Gottlieb, DJ, O’Connor, GT, et al (1995) Elastin and collagen degradation products in urine of smokers with without chronic obstructive pulmonary disease. Am J Respir Crit Care Med 151,952-959[Abstract]
  8. Stone, PJ, Bryan-Rhadfi, J, Lucey, EC, et al (1991) Measurement of urinary desmosine by isotope dilution and high performance liquid chromatography: correlation between elastase-induced air-space enlargement in the hamster and elevation of urinary desmosine. Am Rev Respir Dis 144,284-290[ISI][Medline]
  9. Saltini, C, Hance, Al, Ferrans, VJ, et al (1984) Accurate quantification of cells recovered by bronchoalveolar lavage. Am Rev Respir Dis 130,650-658[ISI][Medline]
  10. Pacholok, SG, Davies, P, Dorn, C, et al (1995) Formation of polymorphonuclear leukocyte elastase: {alpha}1-proteinase inhibitor complex and A{alpha} (1–21) fibrinopeptide in human blood stimulating with the calcium ionophore A231187. Biochem Pharmacol 49,1513-1520[CrossRef][ISI][Medline]
  11. Neumann, S, Hennrich, N, Gunzer, G, et al (1984) Enzyme-linked immunoassay for human granulocyte elastase in complex with alpha 1-antitrypsin proteinase inhibitor. Adv Exp Biol Med 167,379-390[ISI][Medline]
  12. Rennard, SI, Basset, G, Lecossier, D, et al (1986) Estimation of volume of epithelial lining fluid recovered by lavage using urea as marker of dilution. J Appl Physiol 60,532-538[Abstract/Free Full Text]
  13. Brantly, ML, Wittes, JT, Vogelmeier, CF, et al (1991) Use of a highly purified {alpha}1-antitrypsin standard to establish ranges for the common normal and deficient {alpha}1-antitrypsin phenotypes. Chest 100,703-708[Abstract/Free Full Text]
  14. Kueppers, F (1976) Determination of {alpha}1-antitrypsin phenotypes by isoelectric focusing in polyacrylamide gels. J Lab Clin Med 88,151-155[ISI][Medline]
  15. Berger, RL, Hsu, JC (1996) Bioequivalence trials, intersection-union tests, and equivalence confidence sets. Statistical Science 11,283-302[CrossRef]
  16. Sasabuchi, S (1980) A test of multivariate normal mean with composite hypotheses by linear inequalities. Biometrika 67,429-439[Abstract/Free Full Text]
  17. . SAS Institute. (1993) SAS/ETS user’s guide: version 6 2nd ed. SAS Institute Cary, NC.
  18. O’Brien, ML, Buist, NR, Murphey, WH (1978) Neonatal screening for {alpha}1-antitrypsin deficiency. J Pediatr 92,1006-1010[CrossRef][ISI][Medline]
  19. Stoller, JK (1997) Clinical features and natural history of severe {alpha}1-antitrypsin deficiency. Chest 111,1235-1285
  20. . American Thoracic Society. (1989) Guidelines for the approach to the patient with severe hereditary {alpha}1-antirypsin deficiency. Am Rev Respir Dis 27,1494-1497



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