Status: approved; marketed

Organizations involved:

Baxter Hyland Immuno – Manuf.; R&D; Tech.; World mark.

InterMune Inc. – Former

Alpha Therapeutic Corp. – R&D; Tech.; Former

Mitsubishi Chemical Corp. – Former

Yoshitomi Pharmaceutical Industries, Ltd.– Former

Affinity Chromatography Ltd. – Tech.

ProMetric BioSciences, Inc.– Parent

New York Blood Center – Tech.

Cross ref.: See Antitrypsin, alpha-1 Products (#709), and other specific Antitrypsin, alpha-1 product entries.

Description: alpha1-Proteinase Inhibitor (Human) or Aralast (and Aralast NP) is a lyophilized (freeze-dried) formulation of alpha1-proteinase inhibitor (alpha1-antitrypsin; alpha1-PI) purified from fractionated pooled human Plasma, with manufacture including solvent detergent viral inactivation (using tri–n–butyl phosphate and polysorbate 80) and virus removal by nanofiltration. Aralast (and Aralast NP) is prepared from large pools of human plasma using the Cohn–Oncley cold alcohol fractionation process, followed by purification steps including polyethylene glycol (PEG) and zinc chloride precipitations and ion exchange chromatography.

Two versions or variations of Aralast are available - traditional Aralast and more recently-approved Aralast NP. As discussed in the Antitrypsin, alpha-1 Products entry (above), all U.S. licensed alpha1-PI plasma derived products contain chemical modifications which arise during manufacturing and occur in varying levels from product to product. Aralast NP contains approximately 2% alpha1-PI with truncated C-terminal lysine (removal of Lys394), while Aralast contains approximately 67% alpha1-PI with the C-terminal lysine truncation. No known data suggest influence of these structural modifications on the functional activity and immunogenicity of alpha1-PI.

Each vial is labeled with the amount of functional active alpha1-PI it contains expressed as mg/vial. After reconstitution for intravenous administration, the concentration of alpha1-PI is not less than (NLT) 16 mg/mL, and the specific activity is NLT 0.55 mg active alpha1-PI/mg total protein. The reconstituted product contains: elastase inhibitory activity (NLT 400 mg active alpha1-PI/0.5 g vial; NLT 800 mg active alpha1-PI/1.0 g vial; Albumin (Human), not more than (NMT) 5 mg/mL; polyethylene glycol (PEG), NMT 112 µg/mL; polysorbate 80, NMT 50 µg/mL; sodium, NMT 230 mE1q/mL; tr-n-butyl phosphate, NMT 1.0 µg/mLl and zinc, NMT 3 ppm. The product contains no preservatives. Albumin (Human) is apparently used as a stabilizer. The pH is 7.2-7.8.

Aralast (and Aralast NP) is packaged in single dose vials, each containing a labeled amount of alpha1-PI activity (as determined by porcine pancreatic elastase inhibition), along with a vial of Sterile Water for Injection. Aralast is stored at 2-8˚C (refrigerated).

Nomenclature: Antitrypsin, alpha-1/Baxter [BIO]; Alpha1-Proteinase Inhibitor (Human) [FDA]; Aralast [TR]; Aralast NP [SY]; alpha1-antitrypsin [CAS]; 9041-92-3 [CAS RN]; alpha-1 antitrypsin [SY]; AAT [SY]; A1P1 [SY]; A1AT [SY]; alpha1-PI [SY]; proteinase inhibitor, alpha-1 [SY]; NDC 0074-3799-02; NDC 0074-3797-02; NDC 0074-3797-01; NDC 0944-2802-01; NDC 0944-2802-02 [NDC]

Companies.: This alpha-1 antitrypsin product was developed by Alpha Therapeutic Corp., formerly independent, later a subsidiary of Green Cross Corp., Yoshi-tomi Pharmaceutical Industries, Ltd. Alpha was acquired and became a subsidiary of Mitsubishi Chemical Corp. In Oct. 2002, Baxter Healthcare Corp. acquired Aralast and other assets from Alpha/Mitsubishi. Baxter now manufactures Aralast and markets it worldwide. Alpha Therapeutic leased to Baxter the facilities for the production of alpha-1 antitrypsin. Baxter’s acquisition of Aralast allows the company to increase the number of fractions it obtains from each liter of plasma it processes.

In April 2004, Baxter granted InterMune Inc. U.S. co-promotion rights. InterMune's sales force detailed it to pulmonologists for treatment of hereditary emphysema. Intermune terminated this co-promotion in 2005.

Manufacture: Aralast is manufactured from large pools of Plasma using Cohn-Oncley cold ethanol fractionation, with purification including polyethylene glycol (PEG) and zinc chloride precipitations, and ion exchange chromatography. Bulk product is subjected to solvent detergent viral inactivation, involving addition of tri-n-butyl phosphate (solvent) and polysorbate 80 (Tween 80) detergent, which primarily inactivate enveloped viruses, e.g., hepatitis B and C and HIV. The Accumulated Reduction (overall) in virus titers for the manufacturing process is: a) alcohol fractionation – ≥4.8 log for HIV-1, and N/A (not affected/applicable) for bovine viral diarrhea (BVD) virus, pseudorabies virus (PRV), hepatitis A virus (HAV), and porcine parvovirus (PPV); b) solvent detergent treatment – ≥7.2 log for HIV-1; ≥4.8 log for BVD; ≥5.1 log for PRV, and N/A for HAV and PPV; and c) nanofiltration – N/A for HIV-1; ≥6.0 log for BVD, ≥5.5 log for PRV, and ≥5.8 log for PPV.

FDA class: Biologic BLA

CBER class: Blood And Blood Derivatives

Approvals: Date = 20021209; BLA (125039); Indication = augmentation therapy in patients having congenital deficiency of alpha-1-proteinase inhibitor with clinically evident emphysema

Date = 20050909; BLA supplement (correction issued 9/22/2005); Indication = manufacturing change to allow use of Fr.IV1+4 paste as an alternate starting material

Date = 20070504; BLA supplement (STN: 125039/263); Indication = approval of Aralast NP; approval for use of redacted [FDA censored] source material(s) collected from redacted source(s) for manufacture of Aralast by Baxter at a redacted location (consolidation of manufacturing, with Baxter now performing all steps)

Indications: [full text of the "INDICATIONS AND USAGE” section of the Aralast insert/labeling]:

Congenital Alpha1-Proteinase Inhibitor Deficiency

Alpha1-Proteinase Inhibitor (Human), Aralast, is indicated for chronic augmentation therapy in patients having congenital deficiency of alpha1-PI with clinically significant emphysema. Clinical and biochemical studies have demonstrated that with such therapy, Aralast is effective in maintaining target serum alpha1-PI trough levels and increasing alpha1-PI levels in epithelial lining fluid (ELF). Clinical data demonstrating the long-term effects of chronic augmentation or replacement therapy of individuals with Aralast are not available.

Safety and effectiveness in pediatric patients have not been established. Aralast is not indicated as therapy for lung disease patients in whom congenital alpha1-PI deficiency has not been established.

[full text of the "INDICATIONS AND USAGE” section of the Aralast NP insert/labeling]:

Congenital Alpha1–Proteinase Inhibitor deficiency

Aralast NP is indicated for chronic augmentation therapy in patients having congenital deficiency of alpha1–PI with clinically evident emphysema. Clinical and biochemical studies have demonstrated that with such therapy, ARALAST is effective in maintaining target serum alpha1–PI trough levels and increasing alpha1–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 alpha1–PI. Clinical data demonstrating the long–term effects of chronic augmentation or replacement therapy of individuals with Aralast NP or Aralast are not available.

Aralast NP is not indicated as therapy for lung disease patients in whom congenital alpha1–PI deficiency has not been established.

Status: The BLA was approved on Dec. 9, 2002 for treatment of hereditary emphysema. The product was launched in spring 2003. Note, the seven years of orphan status-related marketing exclusivity originally granted to Alpha-1-Proteinase Inhibitor (Human) (Prolastin) from Bayer, now Talacris Biotherapeutics, had long expired.

The May 2007 supplemental approval of Aralast NP included requirements for a Phase IV clinical study to further verify treatment-emergent changes in levels of alpha1-PI, anti-neutrophil elastase capacity, neutrophil elastase (NE), alpha1-PI:NE complexes, neutrophils, and related pertinent analytes in epithelial lining fluid.

Tech. transfer: The Aralast NP product insert cites U.S. 5,616,693; 5,981,715 and other U.S. patents pending.

U.S., 5,616,693, “Process for seperating alpha-1-proteinase inhibitor from COHN IV.sub.1 +1V.sub.4 paste,” was assigned to Alpha Therapeutic Corp., now Instituto Grifols, a subsidiary of Probitas Pharma. This patent describes methods for purifying alpha1-PI involving suspension in an aqueous solution at pH 6, removal of insoluble proteins and resuspension in aqueous solution at pH 8.5; addition of polyethylene glycol (PEG) to precipitate alpha-2 proteins; addition of zinc chloride to the the PEG supernatant precipitate (containing alpha-1-PI) to precipitate crude alpha-1-PI; resolubilizeation and anion-exchange chromatography; with Alpha-1-PI purified by this process having a specific activity about 1.0 units/OD280. U.S. 5,981,715, “Process for increasing the yield of a protein which has been subjected to viral inactivation,” also originally assigned to Alpha Therapeutics, is a division of 5,616,693, with similar coverage.

Aralast has been reported to be manufactured using affinity purification technology originally developed by Affinity Chromatography Ltd. (U.K.), acquired by ProMetric BioSciences, Inc. in May 1999

Solvent detergent viral inactivation technology was developed by and nonexclusively licensed from the New York Blood Center, e.g., see U.S. patent 4,820,805. See the entry for Pooled Plasma, Solvent Detergent Treated (SD Plasma; #799) for further information about solvent detergent viral inactivation, used for inactivation of enveloped viruses (e.g., HIV, hepatitis B and C viruses).

Trials: In Oct. 2004, Baxter reported that ongoing treatment with Aralast augmentation therapy may improve health outcomes and lower healthcare costs for people with alpha1-antitrypsin (AAT) deficiency. Insurance claims for 771 subjects with AAT deficiency were identified in a large healthcare database representing ~12 million covered lives. Of these, 197 also had emphysema. Subjects were stratified according to whether they did or did not receive an AAT therapy commercially available in 2002. A total of 116 (59%) received AAT augmentation therapy. These subjects were less likely to have received outpatient intravenous antibiotic therapy than subjects not receiving AAT (2% versus 14%, respectively; p <0.01) and had fewer hospitalizations per subject (0.3% versus 0.8%; p <0.01). However, AAT subjects also were more likely to have received bronchodilators (91% versus 64%; p<0.01), supplemental oxygen (19% versus 4%; p <0.01) and inhaled corticosteroids (69% versus 44%; p <0.01).

Medical: For chronic emphysema therapy, the recommended dosage is ~60 mg/kg body weight administered once weekly by intravenous infusion.

Market: The 2007 Average Wholesale Price (AWP) for Aralast (not Aralast NP) is $0.41/mg for either 500 or 1,000 mg vials (no change from 2004) (Red Book, 2007).

A single treatment of a typical 50 kg patient consuming the recommended dosage of 60 mg/kg would cost $1,230.00, or about $64,000/year.

Upon its acquisition, Baxter reported that it expected Aralast revenues would be modest in 2004 and grow to approximately $200 million/year within the next five years.