Status: approved; marketed worldwide

Organizations involved:

Leo Pharma A/S – Manuf.; R&D; Tech.; Intl. mark.

Celgene Corp. – USA mark.

Pharmion Corp. – Former

DuPont Pharmaceuticals Co. – R&D; Tech.; Former

Massachusetts Inst. of Technology (MIT) - Tech.

University of Iowa – Tech.

Description: Innohep is a formulation of tinzaparin sodium or low molecular weight fragments of heparin derived from porcine (pig) heparin by enzymatic degradation using heparinase enzymes. Innohep is the only low molecular weight heparin (LMWH) made by enzymatic depolymerization, with other products manufactured by chemical methods. Its average molecular weight is 5,500-7,500 Dalton (5.5-7.5 kDa), with 2/3rds of fragments in the range 2-8 kDa.

Note, this is considered to be a borderline biopharmaceutical product, involving simple enzymatic breakdown of a porcine natural product, heparin derived from dead pig intestines (no living cells/organisms involved, no bioprocessing, no biotechnology up to this stage), subjected to enzymatic breakdown. The resulting low-molecular weight heparin is comparable to low-molecular weight heparin products manufactured by purely chemical methods. For example, Enoxaparin-Na from Sanofi Aventis is produced by alkaline breakdown of heparin; and Dalteparin-Na uses nitrous acid for heparin breakdown.

Each 2 mL vial contains 20,000 anti-Factor Xa (anti-Xa) IU/mL of tinzaparin sodium, a total of 40 IU, and 31. mg/mL of sodium metabisulfite as a stabilizer. The vial contains 10 mg/mL or benzyl alcohol as a preservative. Sodium hydroxide may be added to adjust the pH to 5.0-5.7.

Innohep is unique and cannot be used interchangeably (unit for unit) with heparin or other low molecular weight heparins as they differ in manufacturing process, molecular weight distribution, anti-Xa and anti-IIa activities, units and dosage.

Nomenclature: heparin, enzymatic deriv. [BIO]; Innohep [TR]; tinzaparin sodium [FDA USAN INN BAN]; heparin [CAS for heparin]; 9005-49-6 [CAS RN]; low molecular weight heparin [SY]

Biological.: Like other LMWHs and standard heparin, Innohep does not break up existing blood clots, but rather inhibits the formation of new clots by blocking reactions in the blood that lead to clots. Innohep acts as a potent co-inhibitor of several activated coagulation factors, especially Factors Xa and IIa (thrombin). Its primary inhibitory activity is mediated through an enzyme inhibitor, antithrombin III (AT-III). Innohep also induces the release of tissue factor pathway inhibitor (TFPI), which may contribute to its anticoagulant effect.

Companies.: Innohep was originally developed by DuPont Pharmaceuticals Co., which received FDA approval in 2000. DuPont Pharmaceuticals was subsequently disbanded and its products divested. Pharmion Corporation acquired exclusive U.S. marketing rights to Innohep from LEO Pharma of Denmark in July 2002 and re-launched the product to the U.S. hematology and oncology markets in October 2002. Celgene acquired Pharmion in Nov. 2007.

FDA class: Drug NDA

Approvals: Date = 20000618; NDA

Indications: [full text of the "Indications and USAGE" section of product insert/labeling];

Innohep is indicated for the treatment of acute symptomatic deep vein thrombosis with or without pulmonary embolism when administered with warfarin sodium. The safety and effectiveness of Innohep were established in hospitalized patients.

Status: The NDA was granted on June 18, 2000.

Tech. transfer: Related U.S. patents that appear likely to have been licensed by Leo may include: 5,169,772, "Large scale method for purification of high purity heparinase from flavobacterium heparinum, assigned to the Massachusetts Institute of Technology (MIT) concerning an improved process for purification of active heparinase and heparinase like enzymes from Flavobacterium heparinum; 5,389,539, " Purification of heparinase I, II, and III from Flavobacterium heparinum," assigned to MIT and the University of Iowa, concerning heparinase III that does not does not cleave heparin sulfate; 5,714,376, " Heparinase gene from Flavobacterium heparinum," assigned to MIT, concerning recombinant heparinase I from Flavobacterium heparinum.

Disease: Deep vein thrombosis (DVT) is a term used to describe a blood clot in a major vein, most frequently in the legs. According to the American Heart Association, ~2 million Americans develop deep vein thrombosis annually, and an estimated 600,000 of these develop pulmonary embolism, a potentially fatal complication in which the blood clot breaks free and travels to the pulmonary artery or one of its branches and obstructs blood flow to the lungs. Pulmonary emboli are a major contributory factor in some 10% of all hospital deaths. C ancer patients have an especially high risk of DVT.

Deep vein thrombosis is usually treated with anticoagulants to prevent further clotting of the blood. There are a number of injectable and oral anticoagulant drugs available, and many are used in combination. The anticoagulant heparin has been the standard treatment for DVT since the 1960s. While heparin is an effective therapy, it is most frequently given by intravenous injection and requires careful patient monitoring and dose-adjustment to ensure adequate coagulation without increasing a patient’s risk of bleeding.

Medical: Low molecular weight heparins are used for the treatment of acute symptomatic deep vein thrombosis (DVT) with or without pulmonary embolism in conjunction with the oral anticoagulant warfarin sodium (such as Coumadin) in hospitalized patients.

Treatment of DVT has been transformed with the recent introduction of low molecular weight heparins (LMWH). Studies indicate that LMWHs are as safe and effective as heparin, but have several advantages over heparin therapy. LMWHs have a more predictable anticoagulant dose response. Their greater bioavailability and the longer half-life of LMWHs allow convenient once- or twice-daily dosing via subcutaneous (under the skin) injection by once-a-day administration with dosing based on body weight. Studies show this to be as effective as continuous intravenous, adjusted dose heparin in hospitalized patients for reducing the risk of recurrent thromboembolic events. Studies also indicate that Innohep significantly reduces the risk of major bleeding compared with intravenous heparin.

Market: The low molecular weight heparin Innohep (tinzaparin sodium injection) has been used for over 15 years to treat approximately 30 million patients worldwide