Status: previously being developed as a biogeneric version of Abbokinase; Development halted with Microbix acquiring Abbokinase

Organizations involved:

Microbix Biosystems Inc. – Manuf.; R&D; Tech.; Former

Gensia Labs., Ltd – Former

Angiogen, LLC – Former

Gensia Sicor Pharmaceuticals – Former

Genpharm, Inc. – Parent; Former

Merck KgaA – Parent; Former

BioWhittaker, Inc. – Patent dispute; Former

Cambrex Bio Science, Inc. – Parent; Former

Cross ref.: See the entry for Urokinase/ImaRx (Abbokinase), of which this was intended to be a generic (biogeneric, biosimilar, biocomparable, follow-on) version.

Description: Until early 2008, ThromboClear was being developed be a lyophilized (freeze-dried) formulation of the low molecular weight form of dimeric (two-chain) human urokinase enzyme obtained from culture of neonatal human kidney (NHK) cells. It was intended to essentially be a generic version of Abbokinase, with the company planning to file for an abbreviated 505(b(2)-type approval in the U.S. ThromboClear would be manufactured using a different cell line than that used for manufacture of Abbokinase.

Nomenclature: Urokinase, former/Microbix [BIO]; Urokinase [FDA USAN INN BAN JAN]; ThromboClear [TR]; Urokinase For Injection [FDA]; kinase (enzyme-activating), uro- [CAS]

Companies.: Until concluding a deal to assume manufacture of Abbokinase (see entry above), Microbix Biosystems Inc. had been developing ThromboClear. The company expected to either file for FDA and other (bio)generic approvals, based on similarity to Abbokinase, or decide to delay filings to develop the product for new, broader (unstated) indications:.

Microbix in 1996 originally exclusively licensed manufacturing and marketing rights to Gensia, Inc., a subsidiary of Gensia (later Gensia Sicor Pharmaceuticals), which was acquired by or became Genpharm, Inc., a division of The Merck Generics Group, Merck KgaA. Microbix reported it would receive 35% of gross margin.

In Jan. 2006, Microbix assumed control of manufacture of urokinase from Genpharm Inc./Merck KgaA, including Genpharm/Merck’s urokinase manufacturing facilities in Toronto, Canada. Microbix had also assumed the full costs associated with bringing ThromboClear to market, costs previously funded by Genpharm.

Subsequently, Microbix has fully acquired Abbokinase from ImaRx (see the entry above).

Manufacture: Since this was designed to be a generic version of Abbokinase, it can be presumed to be manufactured by substantially the same process. See the Abbokinase entry above.

Microbix did not respond to inquiries whether it eventually received the BioWhittaker human neonatal kidney (HNK) cell line and was using it for manufacture of ThromboClear. (See the Status section below). The company later reported that it has obtained and was using a different cell line from another undisclosed source (i.e., not BioWhittaker or Abbott). As discussed in the Abbokinase entry, Microbix will now assume manufacture and the NDA for Abbokinase from ImaRx, and will manufacture Abbokinase (i.e., a product with a supplemental NDA as being comparable to prior Abbokinase).

FDA class: Drug NDA

Indications: If ThromboClear had been approved as a generic version of Abbokinase, presumably, its would have been approved for the same indications:.

Status: Microbix had long been developing ThromboClear as a generic biopharmaceutical (biogeneric; biosimilar; biocomparable; follow-on) versions of urokinase (Abbokinase; see entry above) from Abbott Labs., later ImaRx, which is now off-patent. Since Abbokinase was approved as a drug (NDA), Microbix could have applied for approval of ThromboClear as under 505(b)(2) generic drug regulations, with approval based on simialarity to the approved product and with limited clinical trials. 505(b)(2) approvals only require studies and small trials demonstrating comparable identity and bioequivalence (to Abbokinase), rather than requiring full Phase III-type trials to prove safety and efficacy (which is presumed based on similarity to another, previously approved product).

In June 2001, a U.S. District Court ruled in Microbix Biosystems, Inc vs. BioWhittaker, Inc. that Abbott and Bio-Whittaker had violated the Sherman Act (antitrust violation) in refusing to provide human neonatal kidney (HNK) cells to Microbix Biosystems for its development of a generic version of urokinase (ThromboClear). Abbott had entered into an exclusive supply agreement with BioWhittaker after learning about the Microbix’s plans for competing product development. Microbix had initiated this suit in 1997. The District Court’s ruling reaffirmed a lower court’s ruling and injunction requiring sale of human neonatal kidney (HNK) cells by Bio-Whittaker (which supplies these cells to Abbott for manufacture of Abbokinase) to Microbix. The transfer of the cell line did not occur immediately, due to FDA halting of Abbokinase manufacture (see Abbokinase entry), and Microbix having failed to secure its own manufacturing facilities and losing its development partner. No monetary or punitive awards were specified, since the evidence concerning damages at the time was considered “speculative,” with neither of the companies then not manufacturing the product, and due to the other factors affecting Microbix’s difficulties in developing its product After these legal actions, development of Throm-boClear restarted in 2002.

Microbix reports that legal actions delayed its development of ThromboClear by four years. Although, in some respects winning this case, Microbix may not have gained much or anything useful from it. The company refused to answer whether it ever received the disputed HNK cell line from BioWhittacker/Abbott. [As a small public company, it seems likely that the company would acknowledge if it had received the cell line]. The company reports it now uses a cell line from a different undisclosed source.

In May 2006, Microbix reported that “Manufactured batches of ThromboClear are currently undergoing formal analytical and stability testing to prepare data to be included in the filing of an abbreviated new drug application (ANDA) for ThromboClear with the US FDA.” However, Microbix had also made statements that it would abandon this filing, with urokinase (Abbokinase) sales falling in recent years.

Market: As discussed in the Fibrinolytic and Thrombolytic Enzymes entry above, newer recombinant thrombolytic enzymes have and continue to replace urokinase (and streptokinase).

Presuming ThromboClear had been developed in the short-term as a generic version of Abbokinase, Microbix had projected a market size of $200 million for ThromboClear; and ThromboClear would have competed with Abbokinase. Microbix had asserted that because of the technical barriers to entry and increased competition (for a contracting market), another urokinase entrant to the market was not expected (although many companies are reportedly considering developing biogeneric urokinase).