Status - approved; marketed

Organizations involved:

Genentech, Inc. – Manuf.; R&D; Tech.; USA mark.

Schering-Plough Corp. – USA mark.

Merck & Co., Inc. – Parent

Cor Therapeutics Inc. – USA mark.

Millennium Pharmaceuticals, Inc. – Parent

Takeda Pharmaceutical – Parent

Boehringer Ingelheim Pharma KG – Intl. mark.

Chiron Behring GmbH & Co. KG – Europe mark.

Chiron Corp. – Parent

Novartis AG – Parent

Dr. Karl Thomae GmbH – Europe mark.

Kyowa Hakko Kogyo, Ltd. – Japan mark.

Lupin Ltd. – Parent

Mitsubishi Chemical Corp. – Japan mark.

Katholieke Universiteit Leuven –Tech.

Tanabe Seiyaku Co., Ltd. – Former

Parke-Davis Div., Warner-Lambert Co. – Former

Celltech Biologics plc – Patent dispute

Boehringer Mannheim GmbH – Patent dispute

Glaxo Wellcome plc – Patent dispute

Columbia University – Tech.; Patent dispute

City of Hope National Medical Center – Tech.; Patent dispute

Cross ref.: See the Fibrinolytic and Thrombolytic Enzymes entry (#613), and other tPA product entries.

Description: Activase and Cathflo Activase are lyophilized (freeze-dried) formulations of alteplase, a recombinant single chain glycoprotein (type I) form of human tissue plasminogen activator (tPA) produced by a transformed mammalian Chinese hamster ovary (CHO) cell line. Alteplase is identical in primary structure (amino acid sequence) to single-chain or type I human tPA, is composed of 527 amino acids, has a calculated molecular weight of 59,008.71 Daltons (~59 kDa) and molecular formula of C2569-H3894-N746-O781-S40. Alteplase has four possible glycosylation sites, with amino acid numbers 117, 184 and 448 being normally glycosylated; and contains 17 disulfide bonds.

Alteplase is a fibrinolytic/thrombolytic enzyme used for its ability to cause catalytic degradation of fibrin, the major structural component of blood clots or thrombi, e.g., for treatment of acute myocardial infarction (blood clot blockage of arteries supplying blood to heart muscle). Alteplase, like human tPA, enzymatically activates the zymogen (inactive form of an enzyme), plasminogen, to the active enzyme, plasmin, which enzymatically degrades fibrin. Alteplase catalyzes degradation of plasminogen to active plasmin by cleaving a single peptide bond between the amino acids arginine and valine.

The potency of alteplase is expressed in terms of International Units (IU), which have been established in relation to the World Health International Standard. The specific activity of alteplase is 580,000 IU/mg.

Activase is packaged in 50 mg and 100 mg vials for intravenous infusion after reconstitution with Sterile Water for Injection, USP. The 50 mg vial contains alteplase, 50 mg (29 million IU); L-arginine, 1.7 g; phosphoric acid, 0.5 g; and polysorbate 80 (Tween 80), < 4 mg, under vacuum. The 100 mg vial contains alteplase, 100 mg (58 million IU); L-arginine, 3.5 g; phosphoric acid, 1 g; and polysorbate 80, <11 mg. Phosphoric acid and/or sodium hydroxide may be used prior to lyophilization for pH adjustment. Fermentation is carried out in a nutrient medium containing the antibiotic gentamicin, 100 mg/L, but the antibiotic is not detectable in the final product. The dating period when stored at room temperature or 2-8˚C (refrigerated) is 24 months from the date of manufacture, defined as the date of lyophilization in the final product container.

Cathflo Activase, which is a low dose of atleplase solely used to clear blood clot blocked implanted catheters, is packaged lyophilized in vials containing 2.2 mg of Alteplase (includes a 10% overfill), 77 mg of L-arginine, 0.2 mg of polysorbate 80, and phosphoric acid for pH adjustment. Each reconstituted vial delivers 2 mg of alteplase at a pH of ~7.3. The dating period for Cathflo Activase when stored at 2-8˚C (refrigerated) is 18 months from the date of manufacture, defined as the date of final sterile filtration of the final formulated product. Cathflo Activase is supplied as a sterile, lyophilized powder in 2 mg vials.

Note, TNKase (tenecteplase), a next-generation tPA also from Genentech, is replacing Activase as Genentech’s lead thrombolytic therapeutic. Activase is now marketed only for indications: for which no alternatives are available, e.g., emergency treatment of stroke and certain lung clots, and Cathflo Activase is marketed for catheter clearance.

Note, alteplase used by Genentech during early development and clinical trials was primarily composed of two polypeptide chains linked by a disulfide bond (type II tPA). Subsequent development and later clinical trials used the current single chain type I tPA (alteplase). The potency of the one- and two-chain proteins was comparable both in vitro and animal testing. Clinical studies have shown that 100 mg type II tPA is equivalent to 80 mg of type I tPA (alteplase). Pharmacokinetics of the two tPA’s are different, with the clearance of type I tPA (alteplase) being quicker (a desirable characteristic) than type II tPA.

Biological.: Human tPA is produced in the vascular endothelium, but in insufficient quantities to affect blood clot formation or cause significant fibrinolysis. Human tPA can be purified in one of two forms. Both forms display proteolytic and fibrinolytic activity in vitro. Type I (e.g., alteplase) is a single chain structure. Type II is a two chain structure (dimer) with the polypeptide chains linked via a disulfide bond. Type II tPA dimer is derived from the type I form by proteolytic cleavage, which is presumed to occur at the blood clot, i.e., type I tPA (alteplase) is converted to a type II dimerice structure as it activates and converts plasminogen to plasmin.

tPA is a 527-amino-acid serine protease enzyme with 35 cysteine residues that participate in the formation of 17 disulfide bonds. tPA is comprised of five distinct structural domains: a finger region, an epidermal growth factor-like subdomain, two kringle domains, and finally, the catalytic domain.

Alteplase is a serine protease enzyme that converts the zymogen plasminogen to plasmin, a serine protease that degrades the fibrin network in thrombi (clots). Alteplase has high affinity for fibrin, the primary structural component of blood clots, allowing it to selectively bind to fibrin. A “kringle” area positioned upstream from the serine protease portion of tPA plays an important function in binding of alteplase to the fibrin matrix. After injection, alteplase remains relatively inactive (in Type I configuration) until it binds to fibrin (a blood clot). The enzyme’s proteolytic activity is enhanced after binding to fibrin, and the enzyme catalyzes conversion of clot-entrapped plasminogen to plasmin, with the plasmin initiating local fibrinolysis (fibrin break down and clot dissolution) with limited systemic effects. Enhancement of enzymatic activity by binding to fibrin is important, making tPA less likely than many other proteases to cause inadvertent plasmin activation and internal bleeding. inding to fibrin and modulation of the proteolytic activity are primarily mediated by the finger domain and the kringle 2 domain, respectively. As the clot dissolves, plasmin released into the bloodstream is inactivated by plasmin inhibitors. If more plasmin is released than can be neutralized, excess plasmin can digest circulating clotting factor proteins, such as fibrinogen, Factor V and Factor VIII. Extensive digestion of these clotting factors and increased levels of fibrinogen degradation products can result in increased thrombin time (slowing of clotting) and increased risk of diathesis (internal bleeding; hemorrhaging).

Traditional anticoagulant therapy, e.g., with heparin and coumarin, does nothing to directly enhance dissolution of thrombi. Prior to Activase, streptokinase and urokinase were the only available thrombolytic agents. However, each has severe limitations. Neither has a high affinity for fibrin, both activate circulating and fibrin-bound plasminogen relatively indiscriminately, ad the plasmin formed in circulating blood is neutralized rather quickly and lost for useful thrombolysis. Residual plasmin also degrade several clotting factor proteins, causing a hemorrhagic potential. Also, streptokinase is strongly antigenic and patients with high antibody titers respond inefficiently to treatment and cannot remain on continuous treatment. Urokinase therapy was expensive, due to its complex isolation from human urine or tissue culture, and was not widely used.

Nomenclature: tPA, rDNA/Genentech [BIO]; Activase [TR]; Cathflo Activase [TR]; alteplase, recombinant [FDA]; alteplase [USAN INN]; plasminogen activator (human tissue-type 1-chain form protein moiety) [CAS]; 105857-23-6 [CAS RN]; tissue plasminogen activator type I (recombinant human) [SY]; tPA [SY]; rt-PA [SY]; t-PA [SY]; tPA [SY]; fibrinokinase [SY]; Actilyse [TR in Europe, some Asian/Pacific Rim countries]; Activacin [TR in Japan]; GRTPA [TR in Japan]; Actiplas [TR in Italy]; NDC 50242-041-64 and NDC 50242-041-65 [NDC]

Note, the terms tPA, alteplase, Activase, etc., are often used imprecisely, e.g., to refer to tPA in general (human and/or recombinant; type I and/or II), the specific product Activase, and/or alteplase (the active ingredient).

Companies.: Activase and Cathflo Activase were developed and are manufactured by Genentech, Inc., CBER/FDA est. no. 1048. Genentech began development of tPA in 1980. Genentech exclusively markets Activase and Cathflo Activase in the U.S. and Canada. Development of Activase and Cathflo Activase was at least partially funded through Genentech Limited Partners II, L.P. Boehringer Ingelheim KG collaborated in development of Activase, and holds certain international marketing rights.

In Jan. 2001, Cor Therapeutics Inc. and its marketing partner, Schering-Plough Corp. (merged into Merck & Co., Inc. in spring 2009), obtained rights to co-promote both TNKase (a 2nd-generation tPA from Genentech) and Activase for treatment of acute ST-segment elevation (a change in electrocardiogram indicative of myocardial infarction) at U.S. hospitals where the companies currently co-promote Integrilin, a GPIIb/IIIa platelet inhibitor, for acute coronary syndrome indications:. Cor Therapeutics was acquired by Millennium Pharmaceuticals, Inc. In April 2008, Takeda Pharmaceutical Co. acquired Millennium Pharmaceuticals, Inc., and the company continues to operate as an independent subsidiary.

Activase is marketed in many European and other countries (50 total) worldwide by Boehringer Ingelheim KG using the trade name Actilyse, including by its Dr. Karl Thomae GmbH subsidiary in Europe. It is co-marketed by Behringwerke, now Chiron Vaccines (a subsidiary of Chiron Corp., which merged into Novartis AG in late 2005), in Germany, France and Austria, and is marketed in Italy by Dompe. Marketing rights in Japan and other Asian countries have been granted to Kyowa Hakko Kogyo, Ltd. (which markets it as Activacin; now part of Lupin Ltd.) and to Mitsubishi Chemical Corp. (which markets it as GRTPA), which has sublicensed rights to Tanabe. In fall 2006, Tanabe Seiyaku was acquired by and merged into Mitsubishi Pharma.

Final filling and lyophilization of the 50 mg size is performed under contract by Parke-Davis Div., Warner-Lambert Co. (Rochester, MI). [Note, this was reported at time of approval. This facility was later sold to Parkedale Pharmaceuticals; and Warner-Lambert became part of Pharmacia, now merging into Pfizer; and Genentech may now be using other facilities for filling and lyophilization].

Manufacture: Alteplase is produced using the complementary DNA (cDNA) for natural human type I tissue plasminogen activator (tPA) obtained from a human melanoma cell line. A CHO cell line, apparently CHO-K1 (ATCC no. CCL 61), was transfected with a recombinant plasmid containing the gene sequence for expression of alteplase. As described in a paper by an author with Boehringer Ingelheim, plasmid ptPA/DHFR was constructed using a promoter from SV 40 origin and a termination region from hepatitis B virus surface antigen (HbSAg). Genentech uses dihydrofolate reductase (DHFR) as a transfection marker and for amplification of alteplase expression by exposure to methotrexate, with DHFR-transformed cells able to metabolize methotrexate and survive its otherwise toxic effects. This DHFR intron vector was constructed by inserting the mouse DHFR cDNA into the intron of plasmid pRK. A 678 bp blunt-ended fragment containing DHFR cDNA was inserted into the Eco RV sit. The vector transcribes a dicistronic primary transcript containing the murine DHFR cDNA bounded by 5’ splice donor and 3’ splice acceptor intron splice sites, followed by the cDNA encoding tPA. This vector was used to transform CHO cells. The full-length transcript from this vector is translated to produce DHFR, while the spliced portion produces tPA as it only contains the cistron. A tPA gene copy number of about 150 was obtained for tPA gene integration into chromosomes under selective pressure with methotrexate, resulting in a reported tPA titer of 10 µg/mL (equiv. to 1 gram/L). This was increased to 50 µg/mL (equiv. to 5 gram/L) after media optimization. “After a metabolic design of the CHO cell line or their amino acid composition and feeding of the corresponding amino acids at a steady state, the titer could further be improved to 200 µg/mL without changing the microheterogeneity profile of the glycoprotein.”

The host CHO cell line has been adapted to large volume culture and used to prepare the Master Working Cell Bank (MWCB). The MWCB has been shown to remain stable and be free of exogenous microbial (viral, bacterial, mycoplasmal and fungal) contamination. Methods used to test the MWCB include direct cultivation, inoculation of indicator cell lines and animals, hemadsorption, hemagglutination, immunogenicity, enzyme assay, electron microscopy, radioimmunoassay and radioisotopic labeling. Studies have showed that the product obtained from the production cell line remains unchanged over the time it is removed from the MWCB.

CHO cells from the MWCB are cultured at 37˚C in successively larger containers to produce larger quantities of cells (and product). Large-scale fermentation is performed using a suspension cell culture method. This process results primarily in a protein composed of a single type I polypeptide chain (alteplase). The recombinant CHO-expressed tPA used during early development and clinical trials was produced by a small-scale process involving fermentation in roller bottles, with this process resulting in primarily tPA composed of two polypeptide chains linked by a disulfide bond (type II tPA).

The conditioned medium obtained from cell culture is harvested and clarified. Alteplase is isolated by sequential recovery steps and additional purification steps. Purification and other down-stream processing most likely involves the steps of centrifugation of the harvest, homogenization and centrifugation, ultrafiltration, protein refolding, ultrafiltration, anion-exchange chromatography, ultrafiltration, lysine-affinity chromatography (Lys-chromatography), ultrafiltration, and gel filtration chromatography. Lys-chromatography relies on the affinity of alteplase to bind to matrix-bound lysine molecules, with subsequent elution of alteplase from the column.

The recovery and purification process has been validated for removal of DNA, foreign proteins, and culture medium additives, and for inactivation and removal of model retroviruses. In-process controls and analyses for microbial contamination are used to monitor quality.

The final steps of manufacture consist of formulation into the arginine phosphates buffer, pH adjustment with sodium hydroxide and/or phosphoric acid, filling into vials, and lyophilization (freeze-drying). Filling and lyophilization (as reported with original approval) are performed under contract by Parke-Davis, subsidiary of Warner-Lambert Co. . This facility is now Parkedale Pharmaceuticals, Inc., a subsidiary of King Pharmaceuticals.

Final product testing includes viral, mycoplasma, DNA detection, and molecular identity assays (tryptic mapping, specific activity, and protein content assays) of the bulk product. The final product is also tested for appearance, sterility, safety, pyrogenicity, identity, purity, potency, pH, inorganic phosphate content, arginine content, polysorbate content, moisture, and fill volume.

See the Tech. transfer section for further manufacturing-related information.

FDA class: Biologic PLA

CBER class: Blood And Blood Derivatives

CBER to CDER: Among the products transferred within FDA on June 30, 2003

Approvals: Date = 19871113, first approval, PLA/ELA ref. no. 86-236 and 86-236; Indication = treatment of acute ischemic stroke within 3 hours of symptom onset

Date = 1989223; PLA supplement; Indication = for reduction of infract size and mortality associated with acute myocardial infarction

Date = 1999695; PLA supplement; Indication = for treatment of pulmonary embolism

Date = 1996618; PLA supplement; Indication = for the management of acute ischemic stroke in adults, for improving neurological recovery and reducing the incidence of disability

Date = 20010904; BLA supplement; Indication = approval of Cathflo Alteplase

Date = 20020515; BLA supplement; Indication = minor changes in the Activase product insert/labeling

Date = 20050105; BLA supplement; Indication = approval for catheter clearance in pediatric patients

Indications: [full text of "INDICATIONS AND USAGE” section from Activase product insert/labeling]:

Acute Myocardial Infarction - Activase is indicated for use in the management of acute myocardial infarction in adults for the improvement of ventricular function following AMI, the reduction of the incidence of congestive heart failure, and the reduction of mortality associated with AMI. Treatment should be initiated as soon as possible after the onset of AMI symptoms (see CLINICAL PHARMACOLOGY).

Acute Ischemic Stroke - Activase is indicated for the management of acute ischemic stroke in adults for improving neurological recovery and reducing the incidence of disability. Treatment should only be initiated within 3 hours after the onset of stroke symptoms, and after exclusion of intracranial hemorrhage by a cranial computerized tomography (CT) scan or other diagnostic imaging method sensitive for the presence of hemorrhage (see CONTRAindications:).

Pulmonary Embolism - Activase is indicated in the management of acute massive pulmonary embolism (PE) in adults: For the lysis of acute pulmonary emboli, defined as obstruction of blood flow to a lobe or multiple segments of the lungs; For the lysis of pulmonary emboli accompanied by unstable hemodynamics, e.g., failure to maintain blood pressure without supportive measures.

The diagnosis should be confirmed by objective means, such as pulmonary angiography or noninvasive procedures such as lung scanning.

[full text of "INDICATIONS AND USAGE” section from Cathflo Activase insert/labeling; 2/2006]

Cathflo Activase (Alteplase) is indicated for the restoration of function to central venous access devices as assessed by the ability to withdraw blood.

Status: On Jan. 4, 2005, Cathflo Activase received approval from the FDA for catheter clearance in pediatric patients. Cathflo Activase is the only thrombolytic approved for use in both pediatric and adult patients with dysfunctional central venous access devices.

In June 2008, Actilyse receive supplemntal EU approval for thrombolytic treatment of occluded central venous access devices (CVAD), including those used for haemodialysis (similar to Cathflo Activase in the U.S.).

Tech. transfer: U.S. patents assigned to Genentech covering aspects of alteplase and its therapeutic uses include 5,869,314; 4,853,330; 5,849,574; 5,728,565; 5,728,566; 5,869,314; 5,763,253; and 6,284,247. DataMonitor and ABN Amro report that U.S. patent protection for Activase expires in 2005, although the source patent for this is not readily apparent.

U.S. patent 5,869,314 was issued Feb. 9, 1999. The patent has calculated expiration data of Feb 9, 2016. The exemplary claim (no. 1) is: “A tissue plasminogen activator as produced by recombinant expression of DNA encoding said tissue plasminogen activator in transformed host cells.” This covers alteplase. The patent also claims modified versions of tPA, perhaps including reteplase (see Retavase entry).

In Dec. 1996, the European Patent Office upheld Genentech’s main Activase-related European patent in a challenge brought by the Celltech Group plc, Boehringer Mannheim GmbH, (now merged into Roche) and Glaxo Wellcome plc (now merged into GlaxoSmithKline).

U.S. patents including 5,849,574 and 6,261,837, “Human tPA production using vectors coding for DHFR protein,” assigned to Genentech, describe use of DNA sequences encoding for dihydrofolate reductase (DHFR) as a marker for transfection of a sequence coding for tPA protein and to control amplification (selection and expression) of tPA in host cells. Significantly enhanced levels of tPA production are obtained by co-amplification of the tPA gene through treatment of cells transformed with mutant or wild type DHFR with methotrexate. A secondary coding sequence activated by methotrexate is used to control expression of tPA. Expression of DHFR enzyme, which breaks down highly toxic methotrexate, enables survival and selection of properly transformed host cells, while non-transformed cells are susceptible to methotrexate, in a medium deficient in hypoxanthine, glycine, and thymidine (HGT medium).

The Katholieke Universiteit Leuven is reported to receive royalties from sales of Activase. This apparently concerns, U.S. 4,752,603, “Plasminogen activator and pharmaceutical composition having thrombolytic activity,” and related patents assigned to the university, with claims covering purified natural (not recombinant) human t-PA obtained from culture of melanoma cells and its purification. Dr. D. Collen, the sole inventor listed on 4,752,603 is a founder of Thromb-X N.V. The university is now investing its royalties in Thromb-X N.V., now a subsidiary of ThromboGenics, for development of staphylokinase, another thrombolytic agent. The university has reportedly cumulatively received ≥$66 million in royalties from Genentech.

Genentech was a licensee of Columbia University’s patents concerning cotransformation, a broadly-useful genetic engineering method allowing selection and isolation of transformed cells. The original patents and license expired in 2000, but Columbia received another patent in 2002 and was again seeking royalties, which Genentech and other companies challenged in court. Recently, the University decided not to continue to press infringement suits and seek royalties, but the patent office is reexaming the relevant patent, and the university could against pursue infringement and royalties at a later date. See the “Tech. transfer” section of the Recombinant DNA Products entry (#100) for further information.

As discussed in the Recombinant DNA Product entry (at the beginning of this section), Genentech is appealing a $500+ million award to the City of Hope Medical Center (COH) arising from a 1976 contract and patent licensing dispute involving COH developing basic cloning technology for Genentech, including use for tPA. Genentech is appealing to the California State Supreme Court.

Trials: The recent approval for pediatric use was supported by the COOL-2 trial, a Phase IIIb, single arm, open-label study, that enrolled 995 pediatric (> 2 year old and <10kg) and adult patients with CVAD occlusion present for any duration to determine the safety of Cathflo Activase for restoring function to CVADs occluded due to a blood clot. The most serious adverse events reported after treatment were sepsis, gastrointestinal bleeding and venous thrombosis.

Medical: Cathflo Activase is administered by instillation into the dysfunctional catheter at a concentration of 1 mg/mL. For patients weighing ≥30 kg, 2 mg in 2 mL is used; for patients weighing <30 kg, 110% of the internal lumen volume of the catheter is administered, not to exceed 2 mg in 2 mL. If catheter function is not restored at 120 minutes after 1 dose, a second dose may be instilled. There is no efficacy or safety information on dosing in excess of 2 mg per dose for this indication. Studies have not been performed with administration of total doses greater than 4 mg (two 2 mg doses).

Disease: Central venous access device (CVAD) is a broad term that includes many types of catheters (thin, flexible hollow tubes) that are inserted into and positioned within a vein to deliver therapeutics to the bloodstream or withdraw blood for testing. An estimated 5 million central venous access devices (CVADs) or catheters are implanted each year in the U.S. Up to 25% of these devices become occluded (blocked), with 60% of blockages due to a blood clot. Alternative methods for CVAD clearance include invasive techniques, such as surgically removing and replacing the CVAD, which can be an uncomfortable, expensive and risky for patients. But it can be even more dangerous and uncomfortable for patients, if CVADs remain occluded, which can prevent proper administration of needed fluids and medications or require that patients undergo multiple needle sticks to withdraw blood samples.

For its unique stroke indication, Genentech estimates that up to 80% of 700,000 stroke patients in the U.S. annually could benefit from Activase.

Market: Genentech no longer reports sales of Activase and Cathflo Activase, e.g., generally not even mentioning these products in its release reviewing product sales, including them within a “legacy products” classification or combining them with TNKase sales. With Genentech’s introduction of its 2nd-generation tPA product, TNKase (see following entry) the company now reports combined sales figures (for TNKase, Activase and CathFlo Activase.

In late 2012, it was reported that Activase had sales of $494 million, with it uncertain whether this was for 2011 or 2012.

Combined 2006 worldwide sales for Activase and TNKase as reported by Roche, majority owner of Genentech, were CHF 362 million $~$297 million at 7/6/2007 exchange rate), up 15% from 2005 (~$258 million based on 2006 $ data). Total sales were $185.2 million in 2003, and $180.2 million in 2002. Note, TNKase accounts for the great majority of these sales. Combined Activase/TNKase sales were $197 million in 2001; $206 million in 2000; $236 million in 1999; $213.0 million in 1998, $260.7 million in 1997, $294 million in 1996, $301 million in 1995, and ~$180 million in 1991.

Total thrombolytics sales reported by Genentech were $268 million in 2007 and $243 million in 2006..

Recent decreases or lack of growth in Activase sales are due to increased sales of competing thrombolytic agents, e.g., Retavase and TNKase, and a decline in the overall size of the thrombolytic therapy market as some heart attack patients receive mechanical reperfusion rather than thrombolytic therapy.

The 2007 Average Wholesale Price (AWP) is $1,912.80/50 mg vial; and $3,825.61/100 mg vial (Red Book, 2007).

In Canada, Activase is reported to cost $2,746.00 for one 100 mg vial.

Through its much of its life as a therapeutic, Activase was the most widely-used thrombolytic, with marketing in the U.S. and Europe since 1987, particularly for acute myocardial infarction (AMI). It has been administered to >1 million heart attack (AMI) patients. Activase profits were a factor in transforming Genentech into a world class biotechnology company. At its peak, Activase captured 65-70% of the thrombolytics market. In addition, Activase is indicated for the treatment of acute, massive pulmonary embolism, and is still the only emergency therapy approved by the FDA for the treatment of acute ischemic stroke within three hours of the onset of symptoms.

Effective Oct. 1 2004, Medicare changed its policies and now reimburses hospitals specifically for the administration of Activase in ischemic stroke patients. This was hailed by the Wall Street Journal as marking “what promises to create a major change in the treatment of acute stroke patients in the U.S,” although Genentech downplayed this news and characterized the effects of the policy change as “minimal.” Medicare previously reimbursed hospitals at a flat rate of about $5,700 per case of stroke, regardless of whether the Activase was administered. This resulted in hospitals tending not to administer Activase to save money. Under the new regulations, Medicare reimburese hospitals at a base rate of about $6,000 more per stroke case if Activase is administered. Actual reimbursements vary by region and hospital. Medicare intends the extra $6,000 to cover its cost and the additional diagnostic tests and other therapy generally ordered when tPA is used.

Competition: Genentech has positioned TNKase (tenecteplase; a next generation tPA; see related entry) to replace Activase, particularly for its AMI indication. With efficacy comparable to Activase, rapid action, and with an improved safety profile (less risk of hemorrhage at other sites), TNKase primarily competes with Retavase, another next-generation tPA (from Centocor/J&J). Genentech will continue to sell Activase, which remains the only therapeutic approved for emergency treatment of stroke and certain lung clots, and will continue to sell Cathflo Activase (low dose used to dissolve clots in catheters).

In recent years, Cathflo Activase has been the only thrombolytic marketed in the U.S. for clearance of central venous access devices (CVADs) or catheters. Urokinase (Abbokinase; see related entry #626) was previously used for CVAD clearance until the FDA recommended its removal from the marketplace in Dec. 1998 due to inconsistencies in manufacturing by Abbott Labs. Abbokinase was subsequently reapproved, but not with catheter clearance as an approved indication. This product has now been replaced by ThromboClear from Microbix (see related entry), which is used for catheter clearance. Alfimeprase from Protherics (see related entry), upon approval, will be the newest and most advanced thrombolytic for catheter clearance, and will likely capture significant market share (depending on its price).

As an older or more mature product, Activase is now facing biogeneric (follow-on protein, biosimilar, biocomparable, etc.) competition. For example, Transgene Biotek (Hyderabad, India) apparently manufactures a similar or equivalent t-PA product approved in India and, perhaps, other territories (where lack of active patents or their enforcement allows)