Aralast ( Alpha 1-Antitrypsin) - Summary

ARALAST SUMMARY

ARALAST NP is a sterile, stable, lyophilized preparation of purified human alpha₁–proteinase inhibitor (α₁–PI), also known as alpha₁–antitrypsin.¹ ARALAST NP is a similar product to ARALAST, containing the same active components of plasma α₁-PI with identical formulations. ARALAST NP is prepared from large pools of human plasma by using the cold ethanol fractionation process, followed by purification steps including polyethylene glycol and zinc chloride precipitations and ion exchange chromatography. All U.S. licensed α₁-PI plasma derived products contain chemical modifications which arise during manufacturing and occur in varying levels from product to product.¹¹ ARALAST NP contains approximately 2% α₁-PI with truncated C-terminal lysine (removal of Lys394), whereas ARALAST contains approximately 67% α₁-PI with the C-terminal lysine truncation.¹² No known data suggest influence of these structural modifications on the functional activity and immunogenicity of α₁-PI.¹³ To reduce the risk of viral transmission, the manufacturing process includes treatment with a solvent detergent (S/D) mixture [tri–n–butyl phosphate and polysorbate 80] to inactivate enveloped viral agents such as human immunodeficiency virus (HIV), hepatitis B (HBV), and hepatitis C (HCV). In addition, a nanofiltration step is incorporated into the manufacturing process to reduce the risk of transmission of enveloped and non–enveloped viral agents. Based on in vitro studies, the process used to produce ARALAST NP has been shown to inactivate and/or partition various viruses as shown in Table 1 below.²

Table 1: Virus Log Reduction in ARALAST NP Manufacturing Process

Processing Step	Virus Log Reduction Factors
	HIV-1	BVDV	PRV	HAV	MMV
Cold ethanol fractionation	4.6	1.4	2.1	1.4	< 1.0 1
Solvent Detergent-treatment	> 5.8	> 6.0	> 5.5	N/A 2	N/A
15 N nanofiltration	> 5.3	> 6.0	> 5.6	> 5.1	4.9
Overall reduction factor	> 15.7	> 13.4	> 13.2	> 6.5	4.9
HIV-1: Human immunodeficiency virus-1, BVDV (Bovine Viral Diarrhea Virus, model for Hepatitis C Virus and other lipid enveloped RNA viruses), PRV (Pseudorabies Virus, model for lipid-enveloped DNA viruses, to wich also hepatitis B belongs): HAV: Hepatitus A Virus, MMV (Mice Minute Virus, model for small non-lipid enveloped DNA viruses)

Congenital Alpha_{–Proteinase Inhibitor deficiency}

ARALAST NP is indicated for chronic augmentation therapy in patients having congenital deficiency of α₁–PI with clinically evident emphysema. Clinical and biochemical studies have demonstrated that with such therapy, ARALAST is effective in maintaining target serum α₁–PI trough levels and increasing α₁–PI levels in epithelial lining fluid (ELF). ARALAST NP pharmacokinetics are comparable with the pharmacokinetics of ARALAST after single-dose administration in 25 subjects with congenital deficiency of α₁–PI. Clinical data demonstrating the long–term effects of chronic augmentation or replacement therapy of individuals with ARALAST NP or ARALAST are not available.

The effect of augmentation therapy with ARALAST NP on pulmonary exacerbations and on the progression of emphysema in alpha₁-antitrypsin deficiency has not been demonstrated in randomized, controlled clinical trials.

ARALAST NP is not indicated as therapy for lung disease patients in whom congenital α₁–PI deficiency has not been established.

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NEWS HIGHLIGHTS

Published Studies Related to Aralast ( Alpha 1-Antitrypsin)

The fibrinogen cleavage product Aalpha-Val360, a specific marker of neutrophil elastase activity in vivo. [2011.08]
BACKGROUND: Alpha-1-antitrypsin (A1AT) deficiency is the only recognised genetic risk factor for chronic obstructive pulmonary disease (COPD), a leading cause of morbidity and mortality worldwide. Since A1AT is the major inhibitor of neutrophil elastase (NE), this enzyme has become widely implicated in the pathogenesis of COPD in general; however, there is currently no specific biomarker for its pre-inhibition activity. Such a biomarker should be a measure of elastase-specific COPD disease activity with the potential to assess early targeted therapeutic intervention, in contrast to traditional and non-specific disease severity markers such as forced expiratory volume in 1 s... CONCLUSIONS: Aalpha-Val(360) represents the first specific footprint of pre-inhibition NE activity and is a potential biomarker of disease activity and progression in subjects with elastase-dependent COPD. TRIAL REGISTRATION: The EXACTLE study was registered in ClinicalTrials.gov as 'Antitrypsin (AAT) to Treat Emphysema in AAT-Deficient Patients'; ClinicalTrials.gov Identifier: NCT00263887.

Retinoid treatment of Emphysema in Patients on the Alpha-1 International Registry. The REPAIR study: study design, methodology and quality control of study assessments. [2010.12]
Emphysema is characterized by the destruction of alveolar wall and enlargement of alveolar airspaces, resulting in a reduction of the total lung gas exchange area, loss of lung elastic recoil and hyperinflation. The REPAIR study (Retinoid treatment of Emphysema in Patients on the Alpha-1 International Registry) is the first proof-of-concept study of a new potential disease-modifying drug, Palovarotene(c), an orally active, gamma selective retinoid agonist in patients with emphysema secondary to alpha-1-antitrypsin deficiency (AATD) as a model population for the general smoke-induced emphysema population.

Pharmacokinetic comparability of Prolastin(R)-C to Prolastin(R) in alpha-antitrypsin deficiency: a randomized study. [2010.09.30]
BACKGROUND: Alpha1-antitrypsin (AAT) deficiency is characterized by low blood levels of alpha1-proteinase inhibitor (alpha-PI) and may lead to emphysema. Alpha-PI protects pulmonary tissue from damage caused by the action of proteolytic enzymes. Augmentation therapy with Prolastin(R) (Alpha-Proteinase Inhibitor [Human]) to increase the levels of alpha-PI has been used to treat individuals with AAT deficiency for over 20 years. Modifications to the Prolastin manufacturing process, incorporating additional purification and pathogen-reduction steps, have led to the development of an alpha-PI product, designated Prolastin(R)-C (Alpha-Proteinase inhibitor [Human]). The pharmacokinetic comparability of Prolastin-C to Prolastin was assessed in subjects with AAT deficiency... CONCLUSION: Prolastin-C demonstrated pharmacokinetic equivalence and a comparable safety profile to Prolastin. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00295061.

Exploring the role of CT densitometry: a randomised study of augmentation therapy in alpha1-antitrypsin deficiency. [2009.06]
Assessment of emphysema-modifying therapy is difficult, but newer outcome measures offer advantages over traditional methods. The EXAcerbations and Computed Tomography scan as Lung End-points (EXACTLE) trial explored the use of computed tomography (CT) densitometry and exacerbations for the assessment of the therapeutic effect of augmentation therapy in subjects with alpha(1)-antitrypsin (alpha(1)-AT) deficiency...

Prevalence of alpha-1 antitrypsin deficiency in poorly controlled asthma--results from the ALA-ACRC low-dose theophylline trial. [2007.10]
In a study comparing low-dose theophylline to montelukast in poorly controlled asthmatics, 285 subjects consented to be screened for alpha-1 antitrypsin deficiency. Of the 284 for which complete data was available, 10.5% carried a deficiency gene and 2.4% were mildly deficient with an alpha-1 antitrypsin serum level of less than 20 mu M...

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Clinical Trials Related to Aralast ( Alpha 1-Antitrypsin)

A Research Trial of Aralast NP in New Onset Diabetes (RETAIN) - Part II [Withdrawn]
Aralast NP (alpha-1 antitrypsin, AAT), an alpha-1 proteinase inhibitor (human), was the drug to be tested in this clinical trial. Aralast NP is an anti-inflammatory drug that affects the cells that are thought to be involved in the development of type 1 diabetes mellitus (T1DM, T1D). This study, known as RETAIN, was planned as a two-part trial to investigate the effect of Aralast NP on preserving beta cell function and to determine if the intervention would slow the progression of type 1 diabetes. Part I of this trial (NCT 01183468) was an open-label, safety and dose level study consisting of two groups. After completion of Part I, including a satisfactory safety review, enrollment in Part II was to begin. Part II was designed as a two-arm, double-blind, placebo-controlled clinical trial, and participants were to be randomly assigned to either the Aralast NP treatment or placebo group.

A Research Trial of Aralast in New Onset Diabetes (RETAIN) [Terminated]
The drug Alpha-1 Antitrypsin (AAT, Aralast NP) is being tested in this study as an anti-inflammatory drug (a medication that decreases inflammation, which is part of the body's normal ability to fight infection and respond to injuries) that affects the cells thought to be involved in the development of type 1 diabetes mellitus (T1DM, T1D). All subjects enrolled in this study have new-onset T1DM (diagnosis of T1DM within 100 days of Visit 0; T1DM diagnosis fulfilling American Diabetes Association standard T1DM criteria). The focus of Part I of this trial (NCT01183468) is pharmacokinetics (PK), pharmacodynamics (PD) and safety. Upon completion of Part I, including a satisfactory safety review, enrollment in Part II (NCT01183455, Phase II Clinical Trial) will begin.

Safety and Pharmacokinetics of Alpha-1 Proteinase Inhibitor in Subjects With Alpha1-Antitrypsin Deficiency [Completed]
This is a study to assess the safety and pharmacokinetics of weekly infusions of 120 mg/kg of Prolastin-C (alpha1-proteinase inhibitor [alpha1-PI] [Human]), compared to weekly infusions of 60 mg/kg of Prolastin-C in patients with alpha 1-antitrypsin deficiency (AATD).

Comparison of Pharmacokinetic, Safety, Tolerability of Alpha-1 MP and Prolastin In Alpha1-antitrypsin Deficient Adults [Completed]

The purpose of this clinical study (ChAMP - Comparability pharmacokinetics of Alpha-1

Modified Process) is to compare the pharmacokinetic, safety and tolerability of Alpha-1 Proteinase Inhibitor (Human), modified process (Alpha-1 MP) and Prolastin in adult Alpha1-antitrypsin deficient patients. Patients will be infused intravenously with study drug on a weekly schedule for 24 weeks.

Effect of Double Dose of Alpha 1-antitrypsin Augmentation Therapy on Lung Inflammation. [Recruiting]
The current treatment of individuals with alpha-1 antitrypsin deficiency (AATD) who develop lung disease (COPD) is the administration of intravenous purified alpha-1 antitrypsin (augmentation therapy) at a fixed dose of 60 mg/kg per week. This dose aims at increasing the deficient AAT serum levels just above a predetermined "safety threshold" of 11 uM. However, normal levels of AAT are between 25-50 uM. AAT has shown not only to inhibit lung proteases such as neutrophil elastase, but also to modulate inflammation. Given that many subjects with AATD who receive augmentation therapy still have significant lung disease and inflammation, this study will evaluate whether doubling the dose to 120 mg/kg/week has an effect in decreasing lung inflammation. Only the dosing of 60 mg/kg /week has received FDA approval. FDA has granted an IND number to this study to test the higher dose of 120 mg/kg/week. The study will evaluate systemic (serum) and pulmonary (bronchoscopy samples)markers of inflammation in 3 phases: standard dose (4 weeks), double dose (4 weeks) and standard dose (4 weeks).

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Reports of Suspected Aralast ( Alpha 1-Antitrypsin) Side Effects

Death (5),  Abdominal Pain (1),  Asthma (1),  Thrombosis (1),  Pulmonary Mass (1),  Chronic Obstructive Pulmonary Disease (1),  Cardiac Disorder (1),  Liver Disorder (1),  Myocardial Infarction (1),  Alpha-1 Anti-Trypsin Deficiency (1), more >>