Alpha-1-Proteinase Inhibitor (Human) - Prolastin; -alpha1-antitrypsin; alpha1-PI; AAT; A1P1
Status – approved; marketed
Organizations involved:
Talecris Biotherapeutics Inc. – Manuf.; R&D; Tech.; USA mark.=
Instituto Grifols, S.A. – Parent
NPS Pharmaceuticals Inc – Former
Bayer Corp. – R&D; Tech.; Former
Bayer Schering Pharma AG – Intl. mark.; Parent
Cross ref.: See Antitrypsin, alpha-1 Products (#709), and other specific Antitrypsin, alpha-1 product entries.
Description: alpha-1-Proteinase Inhibitor (Human) or Prolastin is a lyophilized (freeze-dried) formulation of alpha1-proteinase inhibitor (alpha1-antitrypsin; alpha1-PI) purified from fractionated pooled human blood Plasma, with manufacture including heat treatment (pasteurization) at 60 ± 0.5˚C as a liquid for not less than 10 hours for viral inactivation.
Prolastin has a specific activity (determined by neutralization of porcine pancreatic elastase) of ≥0.35 mg functional alpha1-proteinase inhibitor/mg protein. After reconstitution with Sterile Water for Injection, USP, for administration by intravenous infusion, Prolastin has an alpha1-proteinase inhibitor/mg protein concentration of ≥ 20 mg/mL, a pH of 6.6-7.4, sodium content of 100-210 mEq/L, chloride content of 60-180 mEq/L; sodium phosphate content of 0.015-0.025 M, polyethylene glycol (PEG) content of not more than (NMT) 5 ppm, and sucrose content NMT 0.1%. Prolastin contains small amounts of other proteins, including alpha2-plasmin inhibitor, alpha1-chymotrypsin, C1-esterase inhibitor, haptoglobulin, antithrombin III (AT-III), alpha1-lipoprotein, albumin, and IgA. Prolastin contains no preservatives.
Prolastin is packaged in single use vials containing either 500 mg or 1,000 mg protein along with 20 mL or 40 mL, respectively, of Sterile Water for Injection, USP. Each vial is labeled with its functionally active alpha1-proteinase inhibitor content as mg/vial. The product is stored at 2-8˚C (refrigerated) or at room temperature (> 77˚F). The dating period is 2 years from the date of manufacture when stored at 2-8˚C. The date of manufacture is the date of the first sterile filtration of the bulk liquid.
Prolastin-C was introduced n 2009. PROLASTIN-C delivers twice the active protein per milliliter as PROLASTIN, cutting infusion volume and time in half when given at the recommended rate of 0.08 mL/kg/min. Clinical studies have shown that PROLASTIN-C and PROLASTIN are comparable, equally effective at raising AAT levels in the blood, and that the adverse event profile of PROLASTIN-C is consistent with that of PROLASTIN. The manufacturing process for PROLASTIN-C incorporates technological advances such as nanofiltration, a virus exclusion technology, and cation exchange chromatography, an additional purification step.
Prolastin-C is supplied in 100 mL single-use vials along with a 20 mL vial of Water for Injection.
Nomenclature: Antitrypsin, alpha-1/Talacris [BIO]; Prolastin [TR original/former]; Prolastin [TR]; Alpha-1-Proteinase Inhibitor (Human) [FDA]; alpha1-antitrypsin [CAS]; 9041-92-3 [CAS RN]; alpha1-trypsin inhibitor [SY]; AAT [SY]; A1AT [SY]; A1PI [SY]; alpha1-PI [SY]; proteinase inhibitor, alpha-1 [SY]; Prolastina [TR in Spain]; CuttActive [TR non-U.S.]; NDC 0026-0601-30; NDC 0026-0601-35 [NDC]
Alpha-1-proteinase inhibitor (alpha1-PI) and alpha1-antitrypsin (AAT) are both used to refer to the product.
Companies.: Prolastin was developed and previously manufactured by Bayer Corp. (now Bayer Schering Corp.), CBER/FDA est. no. 0008, at facilities in Clayton, NC. In April 2005, Talecris Biotherapeutics Inc., CBER/FDA est. 1716, a subsidiary of NPS Pharmaceuticals Inc., acquired the blood/plasma products business of Bayer AG, including manufacturing and U.S marketing, with Bayer AG, now Bayer Schering Pharma AG retaining international marketing.
In Feb. 2011, Grifols S.A./Instituto Grifols acquired Talecris Biotherapeutics.
Manufacture: Each lot of Prolastin starts with more than 1,000 units of Plasma. Prolastin is manufactured from pooled Plasma, which may be obtained from other manufacturers, by modification and refinements of conventional Cohn cold ethanol fractionation. Prolastin is heat treated for viral and other pathogen inactivation at 60˚C for at least 10 hours. In studies using process materials spiked with virus, the heat treatment provided the following log10 reductions in virus titer: poliovirus, 5 logs; herpes simplex virus (HSV), 6 logs; HIV, 3 logs; cytomegalovirus (CMV), 4 logs, vaccinia virus, 4 logs, vesicular stomatitis virus (VSV), 5 logs; porcine parvovirus, 4.5 logs; and visna virus, 6 logs. In spring 2003, Bayer announced that Prolastin manufacturing processes “successfully inactivate vaccinia,” eliminating the risk of vaccinia virus infection from plasma donors receiving smallpox virus vaccinations.
In Nov. 2004, Bayer reported receiving FDA and European Union approvals to operate three additional freeze dryers (lyophilizers) with automated loading and unloading in a new sterile filling facility at its Clayton, N.C, plant used for manufacture of Prolastin.
Talecris has developed an improved manufacturing process for Prolastin, and began comparative pharmacokinetic trials in mid-2006. The new processes “are more efficient processes that better utilize finite plasma sources and further enhance supply. The new process also includes additional viral inactivation/removal steps, such as nanofiltration, for an even greater margin of pathogen safety.”
FDA class: Biologic PLA
CBER class: Blood And Blood Derivatives
Approvals: Date = 19871202, first approval, PLA 86-0255, ELA 86-9481; orphan designation (expired 12/2/1994)
Date - 20030423; BLA supplement; Indication = approval of new sterile filling facility at Clayton, NC
Date = 20091019; BLA supplement; Indication = approval of Prolastin-C
Indications: [full text of the "INDICATIONS AND USAGE” section of product insert/labeling for Prolastin-C, 6/2012]:
PROLASTIN-C is a preparation of alpha1-proteinase inhibitor that is indicated for chronic augmentation and maintenance therapy in adults with emphysema due to deficiency of alpha1-proteinase inhibitor (Alpha1-PI, alpha1-antitrypsin deficiency). The effect of augmentation therapy with any Alpha1-PI product on pulmonary exacerbations and on the progression of emphysema in alpha1antitrypsin deficiency has not been demonstrated in adequately powered, randomized, controlled, clinical trials. PROLASTIN-C is not indicated as therapy for lung disease in patients in whom severe Alpha1-PI deficiency has not been established.
Indications: [full text of the "INDICATIONS AND USAGE” section of product insert/labeling for Prolastin]:
Congenital Alpha1-Antitrypsin Deficiency: Prolastin is indicated for chronic replacement therapy in individuals having congenital alpha1-PI (alpha-1-antityrpsin deficiency; A1AD) with clinically demonstrable panacinar emphysema. Clinical and biochemical studies have demonstrated that with such therapy, it is possible to increase plasma levels of alpha1-PI, and that levels of functionally active alpha1-PI in the lung epithelial fluid are increased proportionately. As some individuals with alpha1-antitrypsin deficiency will not go on to develop panacinar emphysema, only those with evidence of such disease should be considered for chronic replacement therapy with Prolastin. Subjects with PiMZ or PiMS phenotypes of alpha1-antitrypsin deficiency should not be considered for such treatment as they appear to be at small risk for panacinar emphysema. Clinical data are not available as to the long-term effects derived from chronic replacement therapy of individuals with alpha1-antitrypsin deficiency with Prolastin. Only adult subjects have received Prolastin to date.
Prolastin is not indicated for use in patients other than those with PiZZ, PiZ (null) or Pi(null)(null) phenotypes.
Status: For the first 15 years following its FDA approval, Prolastin was the only available AAT augmentation therapy in the U.S.
Tech. transfer: Isolation of alpha-1-proteinase inhibitor from human serum was first reported in 1958. Exemplary patents concerning alpha-1-proteinase inhibitor include U.S. patents 4,379,087 and 4,439,358, assigned to Cutter Labs./Bayer (now Talecris). These disclose methods for separating alpha-1-proteinase inhibitor from a plasma fraction, e.g., Cohn Fraction IV-1, by holding an aqueous solution of the blood plasma fraction at a pH of about 6.5-8, mixing the solution with polyethylene glycol (PEG) at about 8-10% to 23% (wt./vol.) at pH of 4.6-7.5, and increasing the amount of polycondensed polyglycol by 2-3% per 0.5 increase in pH. The alpha-1-proteinase inhibitor is separated from the resulting mixture by centrifugation, recovery of the supernatant solution, contacting the resulting supernatant solution with an anion exchange resin at a pH of 5.5-8.6, and selective elution of alpha-1-proteinase inhibitor from the resin. Alternatively, the alpha-1-proteinase inhibitor may be separated by the further addition of polycondensed polyglycol to precipitate alpha-1-proteinase inhibitor from the mixture following the initial centrifugation of the mixture.
U.S. 4,697,003, “Method of preparing alpha-1-proteinase inhibitor,” Sept. 29, 1987, assigned to Miles Labs., Inc./Bayer (now Talecris), describes improved methods for separating alpha-1-proteinase inhibitor from plasma proteins, especially from Cohn Effluent II & III and Cohn Effluent I. The method includes lowering the concentration of salts (diafiltration and/or gel filtration) and, optionally, alcohol content, contacting the resulting solution with an anion exchange resin (polysaccharide column chromatography adsorbent, e.g., DEAE-Sepha-rose, DEAE-Sephadex, DEAE-cellulose, and QAE-Sephadex from Pharmacia) having selective affinity for alpha-1-proteinase inhibitor to selectively bind the alpha-1-proteinase inhibitor. The alpha-1-proteinase inhibitor is eluted from the column and recovered by contacting the eluate using a polycon-densed polyalkylene glycol with a molecular weight preferably about 3,000-4,000 (e.g., PEG 3350). A carbohydrate is added to the bulk to stabilize the solution during subsequent heat treatment.
U.S. 4,656,254, “Method of Preparing alpha-1-Proteinase and Antithrombin III,” April, 7, 1987, assigned to Miles Labs., Inc./Bayer (now Talecris), describes improvements in the separation and purification of alpha-1-proteinase inhibitor from plasma.
U.S. 5,610,285, “Purification of alpha-1 Proteinase Inhibitor Using Novel Chromatographic Separation Conditions,” March 11, 1997, assigned to Bayer Corp. (now Talecris), describes use of cation exchange flow through chromatography using solutions at pH below 6.0 and low ionic strength for purification of alpha-1-proteinase inhibitor from plasma. Cation exchange chromatography is based on the non-binding of active alpha-1-proteinase inhibitor to the cation column, while other proteins, including denatured alpha1-PI and albumin, do bind to the column. Active alpha-1-proteinase inhibitor flows through the column leaving contaminating proteins bound to the column. Plasma starting material is subjected to anion exchange chromatography, cation exchange flow through chromatography, viral inactivation, cation exchange flow through chromatography, and sterile filtration.
Disease: alpha1-Antitrypsin deficiency (A1AD) is the genetic (inherited) disease associated with low plasma levels of functional alpha1-proteinase inhibitor. A1AD is a chronic, hereditary, usually fatal, autosomal recessive disorder in which a low concentration of alpha1-antitrypsin is associated with slow, severe, panacinar emphysema that most often manifests itself during the third to fourth decades of life. The emphysema is typically worst in the lower lung zones. Prolastin is used for replacement therapy in A1AD to control excess (uninhibited) elastase activity. A1AD mostly affects adults, but also affect infants and young adults. In infants, it causes neonatal cirrhosis which is often fatal. Neonatal hepatitis with cholestatic jaundice occurs in about 10% of newborns with A1AD. In some adults, A1AD is complicated by liver cirrhosis.
Heredity emphysema due to hereditary deficiency of alpha-1 antitrypsin is one of the most common serious genetic diseases. Congenital alpha-1 antitrypsin deficiency (A1AD) affects approximately one in 2,500 people in the U.S. An estimated 1 in 37 persons in the U.S. is a carrier of defective alpha-1-proteinase genes. An estimated 200,000 people in the U.S. and Europe have the deficiency, with about half of these persons symptomatic. Less than 10% of persons with A1AD have been properly diagnosed. The disease is often misdiagnosed as asthma or chronic obstructive pulmonary disease (COPD). The World Health Organization (WHO) recommends that all patients with COPD and asthma be tested for deficiency with a simple blood test. If left untreated, A1AD can lead to liver disease, emphysema and premature death.
Trials: In June 2006, Talecris began trials comparing the AAT produced by new modified manufacturing process to currently available Prolastin to confirm that the pharmacokinetic and safety profiles are comparable in people with alpha-1 antitrypsin deficiency.
In Sept. 2006, Talecris reported that the largest safety data set among alpha-1 antitrypsin augmentation (AAT) therapies compiled over the longest period of time (re)affirmed the clinical safety and tolerability of Prolastin in treating patients with AAT deficiency. Safety data collected since the original approval of Prolastin in 1987 now represent more than 18 years of clinical experience and 40,826 patient-years of exposure. The data show that Prolastin continues to be well tolerated with respect to drug interactions, overdose, and abuse potential.
Medical: Prolastin is used for replacement therapy in persons with genetic deficiency of alpha1-antitrypsin. Prolastin is generally administered intravenously, once per week. Although there is no cure for A1AD-related emphysema, replacement therapy with Prolastin raises the level of alpha-1 proteinase inhibitor in the blood and increases anti-neutrophil elastase activity in the lungs and can slow the progression of lung damage associated with the disease. The recommended dosage is 60 mg/kg body weight once weekly by intravenous infusion. alpha-1-Proteinase has a plasma half-life of 55 hours in cynomolgus monkeys. Replacement therapy has been shown in clinical studies to slow the decline in lung function in A1AD patients with mild to moderate disease.
The threshold level of alpha1-PI in serum required to provide adequate anti-elastase activity in the lungs of patients with A1AD is about 80 mg/dL (based on commercial immunologic standards). Patients with various phenotypes of A1AD with <50 mg/dL endogenous alpha1-PI have over 80% risk for developing emphysema in their lifetime, while those with >80 mg/dL generally have the same risk as the general population.
The recommended dosage for Prolastin-C is 60 mg/kg.
Market: The 2007 Average Wholesale Price (AWP) is $0.40/mg for either the approximate 500 or 1,000 mg vial (Red Book, 2007).
Since its introduction in 1988, PROLASTIN has been the leading augmentation therapy in the United States for people with Alpha-1.
Patients generally purchase the product directly from Bayer (Talecris since April 2005) through its Bayer Direct program, started in Oct. 1999. The program is administered by Express Scripts, one of the largest pharmacy benefits manager (PBM) companies in the U.S. Bayer/Talecris also works with AlphaNet, a not-for-profit organization, to coordinate assistance to enrolled patients.
Because of the scarcity of the protein, related to the complexity of the manufacturing process, supplies are often limited. Some patients seeking AAT, particularly those newly diagnosed, have not been able to obtain it or have experienced significant delays.
Companies involvement:
Full monograph
711 Antitrypsin, alpha-1/Talecris
Nomenclature:
antitrypsin, alpha-1/Talacris [BIO]
Prolastin-C [TR]
Alpha-1-Proteinase Inhibitor (Human) [FDA]
alpha1-antitrypsin [CAS]
9041-92-3 [CAS RN]
A1AT [SY]
A1PI [SY]
AAT [SY]
alpha1-PI [SY]
alpha1-trypsin inhibitor [SY]
proteinase inhibitor, alpha-1 [SY]
CuttActive [TR non-U.S.]
Prolastina [TR in Spain]
NDC 0026-0601-30; NDC 0026-0601-35 [NDC]
FDA Class: Biologic PLA
Year of approval (FDA) = 1987
Date of 1st FDA approval = 19871202
(in format YYYYMMDD)
Biosimilars/biobetters-related U.S. Patents: | expired; 2005 arbitrarily used as the expiration date |
U.S. Patent Expiration Year: | 2011 |
U.S. Biosimilars Data Exclusivity Expiration: | 1999 |
U.S. Biosimilars Orphan Exclusivity Expiration: | 1994 |
U.S. Biosimilars Launchability Year: | 2005 |
U.S. Biobetters Launchability Year: | 2005 |
Biosimilars/biobetters-related EU Patents: | expired; 2005 arbitrarily used as the expiration date; no centralized EU approval, no biosimilars possible |
EU Patent Expiration Year: | 2005 |
EU Biosimilars Data Exclusivity Expiration: | |
EU Biosimilars Orphan Exclusivity Expiration: | |
EU Biosimilars Launchability Year: | |
EU Biobetters Launchability Year: | 2005 |
Index Terms:
biopharmaceutical products
blood products
enteric coating (tablets)
human materials used<!-- humansource -->
Albumin (Human)
alpha1-chymotrypsin
alpha1-lipoprotein
alpha2-plasmin inhibitor
antithrombin III (AT-III)
C1-esterase inhibitor
haptoglobulin
heat treatment (pasteurization)
immune globulin A (IgA)
N-succinyl-L-alanyl-L-alanyl-L-alanyl-p-nitroanilide (SA3 pNA)
Plasma (Human)
polyethylene glycol (PEG)
porcine pancreatic elastase
S-(carboxymethyl)-homocysteine
sodium chloride
sodium phosphate
Sterile Water for Injection
sucrose
virus culture
approval dates uncertain (FDA reports erroneous, conflicting, or simply has lost the original approval dates) (FDAapproved)
orphan status
EU200 Currently Approved in EU
UM001 Marketed Product in US
US200 Currently Approved in US
EM001 Marketed Product in EU
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