Status: approved; marketed

Organizations involved:

The Medicines Co. – R&D; Tech.; World mark.

UCB Pharma, Inc. – Manuf.

UCB Bioproducts S.A. – Parent

Innovex Inc. – USA mark.

Quintiles Transnational Corp. – Parent

Biogen Corp. – R&D; Tech.; Former

Ben Venue Laboratories – R&D; Tech.

Boehringer Ingelheim Pharma KG – Parent

Lonza Biologics plc – Former

New York State Department of Health – R&D.

Cross ref: This is a fully synthetic (not biopharmaceutical) product. See the entry for Hirudin Products (#180) and two recombinant hirudin products (#181 and #182) in the Recombinant DNA Products section.

Description: Bivalirudin is a synthetic peptide anticoagulant composed of 20 amino acids derived from hirudin. See the Hirudin Products entry (#180) for information about hirudin and its anticoagulant activity. Angiomax is packaged in 250 mg vials for intravenous injection. Like the recombinant hirudins marketed in the U.S., lepirudin (Refludan) from Berlex Laboratories, Inc.) and desirudin (Iprivask from Sanofi Aven-tis), bivalirudin is a quick-acting, direct, specific inhibitor of thrombin.

Contrary to many reports in industry newsletters and other sources, the bivalirudin in Angiomax is not a recombinant peptide, nor is it semi-synthetically manufactured from a recombinant peptide. Bivalirudin (Angiomax) is manufactured fully by conventional chemical peptide synthesis (and, as such, is not considered by this author to be a biopharmaceutical). The Medicines Co. had worked with Lonza Biologics plc to develop a 2nd-generation, less expensive manufacturing process using a recombinant intermediate for further chemical synthesis of biva-li-rudin, but there are no plans to change the manufacturing process.

Nomenclature: Hirudin, synthetic [BIO; bivalirudin [FDA]; Angiomax [TR]; Hirulog [TR former]; Efludan [TR former]; BG 8967 [SY Biogen name]

The Medicines Co. changed the trade name from Hirulog to Angiomax in the U.S. and New Zealand in Oct. 1999 to avoid confusion with other similar sounding pharmaceutical products. The company had invited over 12,000 members of the cardiology community to participate in the decision to re-name bivalirudin through a direct mail campaign. Angiomax is one of the first pharmaceutical products to be branded in collaboration with its target clinical community.

Companies.: Angiomax was commercially developed by The Medicines Co. using technology and early trials data licensed from Biogen Corp. (now Biogen Idec). The Medicines Co. and Innovex Inc., a business unit of Quintiles Transnational Corp., co-market Angiomax in the U.S. Biogen collaborated with the Wadsworth Center, New York State Department of Health in the early development of hirulog agents.

UCB Pharma, Inc. division (Cambridge, MA), a subsidiary of UCB Bioproducts S.A. (the Netherlands), manufactures bivalirudin under contract to The Medicines Co. using its Chemilog synthesis process. Analytical methods and processes for the final manufacture of Angiomax were developed by Ben Venue Laboratories, a subsidiary of Boehringer Ingelheim GmbH.

FDA class: Drug NDA

Approvals: Date = 20001218; first approval, NDA; Indication = anticoagulant in patients with unstable angina undergoing percutaneous transluminal coronary angioplasty (PTCA)

Date = 20041130; supplemental NDA; Indication = use in patients with or at risk of heparin-induced thrombocytopenia and thrombosis syndrome (HIT/HITTS) undergoing percutaneous coronary intervention (PCI).

Indications: [full text of the "Indications” section of product insert/labeling, 4/25/2006]:

Angiomax is indicated for use as an anticoagulant in patients with unstable angina undergoing percutaneous transluminal coronary angioplasty (PTCA).

Angiomax with provisional use of glycoprotein IIb/IIIa inhibitor (GPI) as listed in the CLINICAL TRIALS REPLACE-2 section is indicated for use as an anticoagulant in patients undergoing percutaneous coronary intervention (PCI).

Angiomax is indicated for patients with, or at risk of, HIT/HITTS undergoing PCI.

Angiomax (bivalirudin) is intended for use with aspirin and has been studied only in patients receiving concomitant aspirin (see CLINICAL TRIALS and DOSAGE AND ADMINISTRATION). The safety and effectiveness of Angiomax have not been established in patients with acute coronary syndromes who are not undergoing PTCA or PCI.

Status: The NDA was accepted on Feb. 18, 1998, an approvable letter was issued in May 2000, and approval was granted on Dec. 18, 2000 (approval time = ~0.92 year).

Angiomax received its first approval in New Zealand in Sept. 1999 for use as an anticoagulant in patients undergoing coronary balloon angioplasty, and was launched in June 2000. UCB Bioproducts, the manufacturer of bulk bivalirudin, filed a drug master file (DMF) for FDA approval of manufacture using its Chemilog process.

Based on results from the 6,002-patient REPLACE-2 post-marketing Phase IIIb/IV trial (reported in Nov. 2002), The Medicines Co. filed an NDA supplement (sNDA) in Feb. 2003 (and MAA for European Union approval in the first half of 2003) for approval of Angiomax for treatment of unstable angina in patients undergoing coronary angioplasty who have heparin-induced thrombocytopenia/heparin-induced thrombocytopenia thrombosis syndrome (HIT/HITTS). The sNDA was approved in Nov. 2004. In Sept. 2004, the EU granted approval for this indication.

Trials: In March 2006, results were reported from the ACUITY trial of Angiomax (bivalirudin) showed bivalirudin monotherapy superior to heparins (unfractionated or low-molecular weight) plus GP IIb/IIIa inhibitor combination in high risk patients with acute coronary syndromes. The trial met its objectives in favor of Angiomax, including all six of the main pre-specified endpoints. Comparison of ischemic event rates (death, myocardial infarction, revascularization) met the pre-defined criteria for “non-inferiority.” “The ACUITY trial showed that Angiomax alone is as effective as more complicated dual drug regimens, and results in significantly less bleeding, which means improved outcomes for patients.” Results from ACUITY were published in the Nov. 22, 2006, issue of the New England Journal of Medicine.

Tech. transfer: In March 1997, The Medicines Co. exclusively licensed patents and applications from Biogen, Inc. covering bivalirudin, analogs and other novel anticoagulants as compositions of matter, and methods for using Angiomax, Angiomax analogs and other novel anticoagulants.

In mid-2006, after the Medicines Co. missed a non-extendable deadline for filing for a patent term extension for Angiomax by a single day, Rep. W. Jenkins [TN] introduced H.R. 5120 (termed by some the “Dog Ate My Homework Act”) in the U.S. House of Representatives to amend 35 U.S.C. 156, the statute governing patent term extensions based on regulatory review delay. The company filed for a patent extension on drug Angiomax on Feb. 14, 2001, one day later than the application deadline (no later than 60 days after the FDA approves the drug), and wants its patent to be extended 1,773 days, until Dec. 15, 2014. Among the Act’s provisions, the rules would be changed retrospectively and the company would be allowed to file for Angiomax’s patent term extension. This bill was never passed (since there was no noticeable follow-on news, as there surely would be if this single company-oriented earmarked bill had been enacted).

Market: The 2005 Average Wholesale Price (AWP) is $5,150.00/package of 10 vials ($4,562.50 in 2004) (Red Book, 2005).

Competition: Angiomax competes with recombinant hirudin products – Refludan from Berlex Laboratories, Inc. and Iprivask from Sonofi Aven-tis Pharmaceuticals, Inc.

The Medicines Co. expects Angiomax to generate more than $500 million in sales in the U.S. by 2010.