Thrombin, Topical (Recombinant) - Recothrom; rThrombin; rhThrombin
Status: BLA approved in Jan. 2008; MAA withdrawn in EU
Organizations involved:
The Medicines Co. – World mark.
Zymogenetics – Former
Bristol-Myers Squibb Co. – Manuf.; R&D; Tech.; Parent
Bayer HealthCare Pharmaceuticals – Canada mark.
Bayer Schering Pharma AG – Parent
Novo Nordisk A/S – Former
New York Blood Center – Tech.
Cross ref.: See the entries for Thrombin Products (#919) and specific thrombin products, particularly Thrombin-JMI (#920).
Description: Recothrom is a lyophilized (freeze-dried) formulation of recombinant dimeric (2-chain) human thrombin (rhThrombin) produced by enzymatic cleavage of a prethrombin-1 (gla-domainless prothrombin) precursor expressed by transformed Chinese hamster ovary (CHO) cells. The gla-domainless prothrombin (precursor) is a single polypeptide chain secreted into the culture medium that lacks a functional gla domain, includes a portion of the thrombin A chain joined to the serine protease domain, and contains a disulfide-bond between the A chain and the serine protease domain. Upon enzymatic activation, involving cleavages at two specific sites, activated thrombin is formed. This is followed by chromatographic purification, including solvent-detergent treatment and nano-filtration steps dedicated to viral clearance. rhThrombin is identical in amino acid sequence and structurally similar to naturally occurring human thrombin.
Recothrom is packaged in 5 mL vials containing 5000 International Unit (IU) and 20 mL vials containing 20,000 IU as a topical hemostatic agent intended to control excessive bleeding during surgical procedures. Recothrom powder is reconstituted with provided sterile 0.9% sodium chloride injection, USP, yielding a solution containing 1000 IU/mL, pH of 6.0, that is directly applied to bleeding site surface(s) or used in conjunction with absorbable gelatin sponge. The amount required depends upon the area of tissue to be treated. Recothrom vials contain no preservatives. Vials may be strored at 2- 25 °C (36-77 °F).
Nomenclature: Thrombin, rDNA [BIO]; Recothrom [SY]; Thrombin, topical (recombinant) [FDA]; rhThrombin [SY]; rThrombin [SY]; Thrombin, recombinant [SY]; NDC 28400-105-41; NDC 28400-120-41; NDC 28400-120-50 [NDC]
Biological.: Prior to Recothrom, only thrombin derived from bovine blood (Thrombin-JMI), from King Pharmaceuiticals, acquired by Pfizer in Oct. 2010, was available in the U.S. as a stand-alone thrombin product (see the entries for Thrombin Products and Thrombin-JMI); and Evithrom containing human plasma-derived thrombin entered the U.S. market in late 2007.
Thrombin has been used for more than 30 years to control blood loss in a variety of surgical settings. Plasma-derived thrombin is marketed as a component of fibrin sealants (e.g., Tisseel and Hemaseel). However, bovine-derived thrombin has been associated with the development of antibodies (inhibitors) that neutralize thrombin, leading to serious bleeding complications.
Thrombin is a two-chain, disulfide-bonded, glycosylated polypeptide that cleaves specific bonds in fibrinogen to produce fibrin monomers that self-assemble to form a fibrin clot. Human prothrombin is activated to thrombin by two Factor Xa-complex cleavages (to remove the gla and kringle domains and to cleave the A chain from the serine protease domain).
rhThrombin is substantially free of process-derived contaminants and has been characterized extensively in terms of composition, primary, secondary and tertiary structure, enzymatic activity; and in vivo pharmacology. In vivo studies of topical rhThrombin have shown it effective for hemostasis in a rabbit liver excisional wound model.
Prothrombin is a single-chain, vitamin K-dependent glycoprotein that is synthesized in the liver. Prothrombin contains a pro peptide, a gla domain, two kringle regions, an A chain and a serine protease domain. The A chain is disulfide-linked to the serine protease domain. Conversion to thrombin requires that prothrombin be cleaved in two places by Factor Xa-complex. One factor Xa cleavage liberates a protein fragment comprising the gla domain and two kringle regions. The other factor Xa cleavage, which is responsible for producing catalytically active molecule, cleaves the A chain from the serine protease domain to form a disulfide-linked two chain protein. Cleavages at both factor Xa cleavage sites result in the formation of active or activated thrombin (rhThrombin) which is composed of the 49 amino acid, with the A chain disulfide-bonded to the serine protease domain. See the Thrombin Products entry (#919) for further information.
The penultimate step of the blood coagulation cascade is the Factor Xa-complex-catalyzed conversion of prothrombin to thrombin. Thrombin hydrolyzes specific arginyl-glycine bonds in fibrinogen to produce fibrin monomers, which self-assemble into a fibrin clot, and in Factor XIII to produce Factor XIIIa, which in turn cross-links the fibrin monomers to strengthen and stabilize fibrin clots.
Although bovine thrombin (e.g., Thrombin-JMI,) can function in the human clotting cascade, it is recognized as foreign by the human immune system and can induce antibodies, resulting in loss of thrombin efficacy and bleeding. Other proteins present in the bovine product may trigger antibody responses. In some cases, antibodies produced against bovine proteins cross-react with homologous human proteins and lead to significant bleeding disorders. rhThrombin is being developed as an alternative to the bovine-derived product for the control of surgical bleeding. Recombinant product should also reduce the risk of bovine and other animal viruses and prions.
Companies.: Development of rhThrombin began when ZymoGenetics was still a subsidiary of Novo Nordisk A/S. ZymoGenetics later became an independent, publicly-traded company; and is now part of Bristol-Myers Squib (BMS; acquired in Oct. 2010). ZymoGenetics, CBER/FDA est. no. 1758, manufactures Recothrom.
In June 2008, Bayer Schering exclusively licensed ex-U.S. (international) marketing rights for rhThombin. Bayer paid ZymoGenetics $30 million up from and will potentially pay as much as $168 million in milestone payments, in addition to royalties up to 20% on non-U.S. sales. Both Bayer and ZymoGenetics will co-market the product in the U.S. for three years after approval, during which ZymoGenetics pays Bayer royalties of as much as 20% of U.S. sales in those years, plus as much as $20 million in milestone payments if the drug reaches sales goals. Bayer will receive royalties at a lower rate for two years after the U.S. co-promotion period ends. Bayer will contribute 70 sales reps and 25 medical science liaisons to the U.S. marketing effort, while ZymoGenetics will pay for 48 sales reps and six medical liaisons.
In Dec. 2009, ZymoGenetics and Bayer Schering Pharma AG restructured their U.S. co-promotion and ex-U.S. licensing and collaboration agreements. Effective Jan. 1, 2010, ZymoGenetics regained full promotion rights in the United States and all ex-U.S. rights except in Canada, where Bayer will market and sell the product. Thus, Bayer Schering only markets Recothrom in Canada. Beginning in 2010, Bayer received a reduced sunset period commission through Dec. 31, 2011, which was previously capped at $25 million per year and now will be subject to an aggregate maximum of $12 million. ZymoGenetic is no longer required to pay Bayer U.S. sales bonus payments totaling $20 million, which were anticipated to have been payable in 2010 and 2011 or upon termination of the co-promotion agreement. In Canada, Bayer sells the product and pays royalties on net sales to ZymoGenetics. Bayer is no longer required to pay ZymoGenetics up to $16 million in milestone payments for ex-U.S. regulatory approvals. ZymoGenetics assumed responsibility for all active regulatory files in countries besides Canada.
In Dec. 2012, The Medicines Company licensed exclusive marketin rights from BMS. he Medicines Co. also markets Angiomax, a thrombin inhibitor. It was reported that "Under terms of the agreement, The Medicines Company will pay Bristol-Myers Squibb an upfront collaboration payment of $105 million and an upfront option fee of $10 million. The Medicines Company has also agreed to pay Bristol-Myers Squibb a tiered royalty on annual net revenues of Recothrom during the two-year collaboration term. Bristol-Myers Squibb will retain responsibility for the manufacturing of Recothrom and will be The Medicine Company’s exclusive supplier of Recothrom during the term of the agreement. The option enables The Medicines Company to acquire the Recothrom assets for a purchase price based on average net sales during the two-year collaboration term."
Manufacture: See the Tech. transfer section. manufacture does not involve any products of animal or human origin.
FDA class: Biologics BLA
Approvals: Date = 2008-117; BLA (STN: BL 125248/0)
Indications: [Full text of the " "Indications and USAGE" section of product insert/labeling];
RECOTHROM Thrombin, topical (Recombinant), is indicated as an aid to hemostasis whenever oozing blood and minor bleeding from capillaries and small venules is accessible and control of bleeding by standard surgical techniques is ineffective or impractical. RECOTHROM may be used in conjunction with an absorbable gelatin sponge, USP.
Status: On Dec. 15, 2006, Zymogenetics filed a BLA for rhThombin (5,000 Unit vial) as a general aid to achieving hemostasis during surgery. This was accepted for review on Feb. 15, 2007, with a Prescription Drug User Fee Act (PDUFA; target approval) date of Oct. 18, 2007.
In March 2007, ZymoGenetics reported that FDA will not require additional clinical trials for approval of rhThrombin spray as an aid to controlling bleeding during surgery. Approval of a spray device combination will be subject to acceptance of a Prior Approval Supplement (PAS) to be submitted after the approval of the initial BLA for rhThrombin (vial). ZymoGenetics plans to file a PAS for a 20,000 Unit vial and a 20,000 Unit spray kit immediately after approval of the 5,000 Unit vial. PASs cannot be filed until the original product is approved and require FDA action within four months of filing.
On Aug. 22, 2007, Zymogenetics reported that FDA considered additional manufacturing information it submitted to be a major amendment to the BLA, and extended the BLA;s review by three months to Jan. 17, 2008.
In Dec. 2007, King Pharmaceuticals, the U.S. marketer of Thrombin-JMI, filed a "citizen's petition" with FDA seeking to delay or halt approval of rhThrombin, alleging insufficient data are available to support it safety, efficacy and accelerated approval, and seeking to bar any claims of superiority for rhThrombin.
FDA-required post-marketing studies include deferred pediatric studies required under section 2 of the Pediatric Research Equity Act (PREA) are considered required postmarketing study commitments, with a study protocol submitted by June 2008 and final report by Dec, 2010.
Please submit final study reports to this BLA. ZymoGenetics must also conduct a postmarketing study to evaluate immunogenicity and safety of re-exposure. This protocol must be submitted 90 days following approval, with first patient first visit (FPFV) ~6 months following approval of the protocol and last patient last visit no later than 25 months after FPFV.
rhThrombin is the first product ZymoGenetics has developed fully on its own. It is marketed without the black box warning regarding induction of human thrombin antibodies included in the product insert/labeling for bovine thrombin (Thrombin-JMI).
In April 2008, FDA reported that information at Zymogenetics' Web site, including a press release, was "false or misleading because it omits material facts about Recothrom." FDA disagreed with the statement, "A Phase 3 pivotal clinical trial showed that Recothrom had comparable efficacy and a significantly lower incidence of antibody formation compared to the commercially available bovine thrombin product.” "This statement is false or misleading because it suggests that Recothrom is safer than the bovine thrombin product due to a lower incidence of antibody formation in the patients who took the Recothrom...Indeed, according to the "Immunogenicity" section of the Recothrom PI, the development of antibodies in either group did not lead to any adverse events such as excessive bleeding. In addition, according to the “Adverse Reactions” section of the PI, the incidences of pre-specified adverse events were similar between Recothrom and bovine thrombin." ZymoGenetics then added a footnote to a release on its Web site stating, "In the Phase 3 pivotal clinical study comparing Recothrom to bovine thrombin, adverse events were reported with similar frequency in both treatment groups. No reported adverse events were considered causally related to antibody formation in either group."
In Dec. 2009, Bayer Schering Pharma withdrew its Marketing Authorization Application (MAA) to the European Medicines Agency (EMEA) for approval to market Recothrom in Europe. EU authorities had indicated that they would require additional clinical trial data for approval. Thus, approval and market introduction of Recothrom in Europe is at best a few years off, and the major market for bovine thrombin will remain the U.S.
Tech. transfer: The U.S product insert cites coverage by U.S. 5,476,777; 5,502,034; 5,527,692 and other U.S. patents pending.
rhThrombin-related U.S. patents assigned to ZymoGenetics include 6,780,411, “Tissue sealant compositions; and 5,527,692; 5,502,034 and 5,476,777, each entitled, “Methods for producing thrombin.” The later three patents claim methods for manufacture of rhThrombin using DNA constructs including a transcriptional promoter, a DNA sequence encoding a human gla-domainless prothrombin, and a transcriptional terminator. The expressed thrombin precursor includes a signal sequence selected from human tissue plasminogen activator leader sequence, the human alpha-2 plasmin inhibitor signal sequence, the Saccharomyces cerevisiae BAR1 secretory signal sequence or the Saccharomyces cerevisiae MF.alpha.1 signal sequence. The gla-domainless prothrombin comprises kringle 1, kringle 2, the A chain, an activation site and the serine protease domain of prothrombin; kringle 2, the A chain, an activation site and the serine protease domain of prothrombin; or the A chain, an activation site and the serine protease domain of prothrombin. The gla-domainless prothrombin activation site is readily cleavable (forming rhThrombin) by a snake venom activator, thrombin, or the Saccharomyces cerevisiae KEX2 gene product.
Activated thrombin produced from gla-domainless prothrombins that are activated in the secretory pathway or are activated in the culture medium may be purified by chromatography using para-aminobenzamidine coupled to a solid matrix as described above.
Purified thrombin precursors may be activated using a venom activator from a viper such as Echis carnatus or Vipera russellii, preferably from Echis carnatus as described by, for example Alternatively, purified thrombin precursors may be activated using Factor Xa essentially as described, for example, by Heldebrant et al. (J. Biol. Chem, 248: 7149-7163 (1973)), Downing et al. (J. Biol. Chem. 250: 8897-8906, (1975)), and Krishnaswamy et al. (J. Biol. Chem. 262: 3291-3299 (1987)). Thrombin precursors that contain a thrombin activation site may be activated by the addition of thrombin. Activated material is preferably purified using an S-Sepharose fast flow column and a salt gradient, preferably from 100 mM to 1M. The purified activated material may be further purified by reverse phase HPLC
U.S. 6,780,411 has only two claims: “1. A method for producing a fibrin sealant comprising mixing a human recombinant fibrinogen, recombinant human thrombin, recombinant human factor XIII and calcium ions together, wherein the fibrinogen is present at a concentration in solution of 20-30 mg/ml, the factor XIII is present in solution at a concentration of 3-10 .mu.g of factor XIII per mg of fibrinogen present in solution, the thrombin is present in solution at a concentration of 5-300 I.U./ml, the calcium ions are present in solution at a concentration of 5-20 mM, and wherein sucrose is mixed at a concentration of about 4.5% with the fibrinogen, the factor XIII, the thrombin and the calcium. 2. A fibrin sealant produced according to the method of claim 1.”
The New York Blood Center holds key U.S. patents concerning solvent-detergent viral inactivation. See the Plasma SD entry (no. xxx) for further information. ZymoGenetics has taken a license from the Center (unless/until its patents have expired).
Trials: Overall, in its trials, the primary endpoint has been non-inferior incidence of hemostasis within 10 minutes compared with bovine-derived thrombin (Thrombin-JMI). Phase III trials are comparing rhThrombin against bovine-derived thrombin in over 400 patients.
In June 2005, results were reported from two randomized, double-blinded Phase II trial in patients undergoing either arteriovenous grafting surgery for hemodialysis access or peripheral artery bypass surgery. These two vascular trials were part of a four-part Phase II clinical study program for rhThrombin, which also included spinal and liver resection surgeries. Sixty patients had gelatin sponges saturated with either rhThrombin or placebo applied to sites of bleeding during surgery. Assessments were made to determine the time at which bleeding was stopped by either treatment. Patients with continued bleeding at the selected sites after ten minutes were given further treatment with open-label rhThrombin or other hemostatic measures at the discretion of the surgeon. The primary objective was the safety of rhThrombin as a surgical hemostat. Secondary objectives included determinations of immunogenicity and point estimates of time to hemostasis. Anti-product antibodies were measured by ELISA at baseline and 1 month posttreatment.
The primary endpoint was met, with rhThrombin safe and well-tolerated. Only one of 37 rhThrombin patients (2.7%) produced detectable antibodies to thrombin. This compares favorably to published results of studies involving bovine thrombin, in which over 40% of treated patients generated antibodies to the bovine product. Rescue hemostasis with rhThrombin at sites with continued bleeding at ten minutes was effective in over 90% of (twelve of thirteen) cases in which it was used. Ninety percent of rhThrombin-treated bleeding sites achieved hemostasis by ten minutes, compared to only 74% of those treated with placebo. The average time to hemostasis in rhThrombin-treated patients was 27% lower than in patients treated with placebo.
Overall results from Phase II studies were reported in Journal of Thrombosis and Haemostasis 2005; Vol. 3, Sup. 1: abstract P1441. “A total of 130 subjects were enrolled in the four studies. In a preliminary analysis conducted after 80 subjects completed treatment, the most common adverse events included postprocedural pain, nausea, constipation, and pyrexia. rhThrombin appeared to be safe and well tolerated, with a favorable immunogenicity profile. A hazard ratio of 1.3 was estimated for the comparison of time to hemostasis for rhThrombin + gelatin sponge versus placebo + gelatin sponge, indicating that rhThrombin has a positive impact on hemostasis.”
Results from the pivotal Phase III trial were reported in Sept. 2006. The randomized, double-blinded trial was conducted at 34 sites in the U.S. and evaluated the product in the same four types of surgery examined in Phase II studies: spinal surgery, liver resection, peripheral artery bypass and arteriovenous graft construction. The 411 patients were randomized to receive rhThrombin or bovine thrombin (Thrombin-JMI). Enrollment was balanced among surgery types according to study protocol, with 122 patients in spinal surgery, 125 in liver resection, 88 in peripheral artery bypass and 76 in arteriovenous graft construction. The study was designed to support broad product labeling for the use of rhThrombin as an aid to controlling bleeding during surgery. The primary endpoint of the study was a comparison of the efficacy of rhThrombin versus bovine thrombin, as measured by the overall percentage of patients achieving hemostasis within 10 minutes.
The study met its primary endpoint, with rhThrombin achieving hemostasis within 10 minutes 95.4% of the time and bovine thrombin 95.1% of the time. Among the four types of surgery evaluated, the incidence of hemostasis within 10 minutes was similar between groups. Superior immunogenicity was seen with rhThrombin, based on a significantly lower incidence of post-treatment antibodies. The incidence of baseline positive anti-product antibody titers was lower for subjects receiving rhThrombin than with bovine thrombin (rhThrombin, 3/198 or 1.5%; bovine thrombin, 10/200 or 5%). The incidence of post-treatment anti-product antibody development was significantly lower in the rhThrombin group (rhThrombin, n=3/198 or 1.5%; bovine thrombin, n=43/200 or 22%) (p < 0.0001). The incidence and severity of adverse events observed in the Phase III study were similar between treatment groups.
Overall, in Phase I through III studies, rhThrombin showed a rate of antibody development of 1.4%, which was comparable to that seen with placebo (2.4%) in Phase II clinical trials. The most common adverse events occurring in patients treated with rhThrombin and bovine thrombin included incision site complication, nausea, procedural pain, constipation and vomiting. These adverse events are not uncommon in patients undergoing the types of surgeries evaluated in the study. Serious adverse events were experienced by 18% of patients exposed to rhThrombin (n=36); and 22% of those receiving bovine thrombin (n=46).
Some stock analysts have noted anecdotal reports of patients vomiting during trials of rhThrombin. However, the connection between topically applied thrombin and nausea or vomiting is tenuous, and there is no known systemic effect from thrombin that would result in nausea or vomiting. This does not appear to be serious issue.
Medical: Recothrom is used as an aid to hemostasis whenever oozing blood and minor bleeding from capillaries and small venules is accessible and control of bleeding by standard surgical techniques is ineffective or impractical. Recomthrom is applied on the surface of bleeding tissue only. The volume of reconstituted Recothrom required will vary, depending on the size and number of bleeding sites to be treated and the method of application. The healthcare professional should determine the number of vials required to produce a sufficient volume of reconstituted product
In its pivotal trial in 411 patients, about 1.5% on rhThrombin developed antibody reactions against it, a much lower rate than with Thrombin-JMI. The official labeling notes, " No specific adverse events have been established as adverse reactions causally related to RECOTHROM administration. In a clinical study comparing RECOTHROM to bovine thrombin, adverse events were reported with similar frequency in both treatment groups. The most common event was incision site complication. Limited data (n=6) are available on repeat exposure to RECOTHROM." Recomthrom, unlike its bovine thrombin competitors, has no Black Box safety warning.
Market: Besides Thrombin-JMI, Recothrom also competes to some extent with Evithrom, containing human plasma-dervied thrombin. Thrombin-JMI is the main competition. Thrombin-JMI and Recothrom both have better safety profiles than human plasma-derived thrombin (Evithrom), which inhibits its sales. With the thrombin market relatively mature and rather constant or only slowly growing (particularly, without approvals in Europe), nearly all gains in sales of Recothrom involve loss of U.S. sales by Thrombin-JMI.
Prior to Recothrom approval, thrombin (i.e,. bovine-derived Thrombin-JMI from King Pharmaceuticals) was used in over 500,000 surgeries per year in the U.S., according to ZymoGenetics, while other sources, e.g., an enthusiastic stock analyst, report bovine-derived thrombin is used annually in over 700,000 surgeries in the US, and more than 1,000,000 worldwide. Thrombin (bovine) is also a component in a number of surgical sealants (fibrin sealants; see related entries). So far, nearly all Recothrom sales have been in the U.S., with Recothrom not yet approved in the European Union (EU), its other potential major market
The Oct. 2010 acquisition of ZymeGenetics by now Bristol-Myers Squibb may improve the marketing and sales of Recothrom.
rhThrombin had been expected by most analysts to rapidly replace King Pharma’s bovine-derived hemostat, Thrombin-JMI (see related entry). Analysts' projections of rhThombin sales have varied greatly. Most projections of peak sales are on the order of $500 million/year. Upon approval, Piper Jaffray & Co. had estimated a market of $308 million in 2010.
The 2009 market for purified thrombin was ~$228 million [Recothrom, Thrombin-JMI, Evicel and GELFOAM Plus (collagen soaked with human thrombin/ Evicel)]. Total sector sales were $267 million in 2007, and ~$246 million in 2006. Thus, the overall market has remained rather steady in recent years.
Recothrom (recombinant human thrombin), costs about $86/vial when purchased through long-term contracts. This is about twice the cost of Thrmobin-JMI. ZymoGenetics claims that the extra cost for recombinant thrombin is negligible when compared with other surgical costs (but avoids making direct cost comparisons with Thrombin-JMI).
Hospitals are the only market for tissue sealant products, which are only used by surgeons and not available by prescription. About 1,000 hospitals in the U.S. account for 90% of all thrombin products sales.
Recothrom has been having difficulty in ramping-up sales and taking market share from Thrombin-JMI. This is highly unusual for recombinant proteins entering the market in competition with legacy animal-derived products.
Recothrom achieved only $29.6 million sales, 13% market share (by $dollars) in 2009, its first full year on the U.S. market, despite being approved in Jan. 2008 and being in the U.S. market for nearly two years by the end of 2009. This appears to be a historic low for market penetration and replacement/displacement by a recombinant protein of an analogous animal-sourced product in the U.S. (and European) market. Total net sales by ZymoGenetics were $8.8 million in 2008 (partial year only).
Recothrom total sales of about $51 million are projected for 2010 by ZymoGenetics, a 172% increase, but still a slow market share uptake rate for a recombinant protein replacing its animal-sourced analog
In 2009, Recothrom had only 13.0% U.S. market share (by dollars, not units sold). With Recothrom costing about twice as much as Thrombin-JMI, this indicates that the market share by unit sales for Recothrom was a rather pitiful 6-7%, not really much sales or market penetration at all by biopharmaceutical standards. Despite this, illustrating the high profit margins with these products, ZymoGenetics expects to "reach breakeven levels in 2010" with projected 2010 sales of ~$51 million. The U.S. market share for Recothrom vs. Thrombin-JMI appear to be slowly increasing, e.g., first quarter 2010 sales were 19% market share (by $).
ZymoGenetics claims significant advantages for Recothrom, vs. Thrombin-JMI. The primary one is the total lack of bovine Factor V/Va and associated antibody induction (seroconversion) problems. However, the lack of hard head-to-head clinical data linking higher antibody levels with more adverse events is one factor slowing Recothrom's market penetration. Recothrom is also claimed to lack the viral and prion infection hazard associated (theoretically) with human blood-derived both Thrombin-JMI and Evithrom. ZymoGenetics' marketing also notes the black box warnings associated with these other products.
Recothrom annual sales have been projected by some analysts to likely reach $300 million within three to five years, i.e., capture the entire and a growing market for topical thrombin. Some more overly optimistic analysts project a total market of $600 million. However, with thrombin and fibrin sealant kits having to compete with other much less expensive sealants, such as cyanoacrylate glues, this near tripling of the thrombin market may not be realistic.
Most analyst projections presume that Recothrom will substantially replace Thombin-JMI as the clear thrombin market leader. However, even assuming a lack of new evidence clearly showing increased risks or problems with Thrombin-JMI, many higher estimates for Recothrom sales appear excessive. This analyst estimates that in five years, 2015, the total thrombin market may be about $350 million, with Thrombin-JMI retaining about 33% market share by number of units sold ($113 million/year), with market share based on total sales even lower (with Recothrom projected to always be sold at a premium relative to the natural product). The Stanford Group projects King's thrombin to could fall to $88 million, or about 15% thrombin market share, by 2012 (presuming a total market of $586 million), mainly because of competition from Recothrom. However, on a longer term basis, e.g., by 2015, Recothrom (and by then also possibly biosimilars/biogenerics) will have captured nearly all the thrombin market (presuming Thrombin-JMI is still being manufactured).
Thrombin-JMI (see related entry for this boving blood-derived thrombin) is the primary competition for rhThrombin, but is not marketed in Europe. Thus, Europe is expected to become a major market for rhThrombin. Another recently-approved bovine plasma-derived thrombin from Omrix and marketed by Johnson & Johnson also competes against both Thrombin-JMI and rhThrombin. rhThrombin has advantages in safety over the plasma-derived products, but the extent to which ZymoGenetics can actively make such claims and their impact on sales remains to be seen.
Purchasing decisions regarding topical coagulants to be used in surgery generally reside with surgeons. These purchasing decisions are complicated or skewed (from ZymoGenetics' perspective) in favor of Thrombin-JMI due to its lower costs, about half the price of Recothrom. ZymoGenetics and many others note that while surgeons generally make the purchasing and use decisions, they rarely ever see or even know about adverse events occurring later (takes weeks to develop antibodies), with hematologists the ones that have to deal with these problems. Where hematologists have a significant say in topical coagulant purchasing decisions, almost all favor Recothrom with its total lack of problematic traces of residual Factor V/Va..
With its recombinant source, superior safety profile and the potential absence of a black box warning, rhThrombin will eventually become the topical agent of choice as an adjuvant to hemostasis during surgery. The use of topical thrombin in surgical procedures could increase from 17% of current surgical procedures to about 50% of these procedures by 2012, with a market of about $500 million.
Companies involvement:
Full monograph
261 Thrombin, rDNA
Nomenclature:
Thrombin, rDNA [BIO]
Recothrom [TR]
Thrombin, topical (Recombinant) [FDA]
Thrombin, alpha [EU]
rhThrombin [SY]
Thrombin, recombinant [SY]
NDC 28400-105-41; NDC 28400-120-41; NDC 28400-120-50 [NDC]
molecular weight (kDa) = 36
FDA Class: Biologics BLA
Year of approval (FDA) = 2008
Date of 1st FDA approval = 20080117
(in format YYYYMMDD)
Index Terms:
biopharmaceutical products
recombinant DNA
alpha granules
Chinese hamster ovary (CHO) cells
Factor Xa
mammalian cell culture
PrefGel
prothrombin, bovine
Saccharomyces cerevisiae (yeast)
tissue culture, three-dimensional
lyophilized (freeze-dried)
Namalva cells
sodium chloride
viral inactivation, solvent detergent
North American coral snake
North American coral snake
EU003 EU application withdrawn
UM001 Marketed Product in US
US200 Currently Approved in US
EM999 Not Available/Not Marketed in EU
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