Spotlight On... Anti-Thrombotics, A Review of Jan-Mar 2011-- Pharma Matters Report

Spotlight on...Anti-thRoMBotiCSA phARMA MAttERS REpoRt.A REVIEW OF JANUARY-MARCH 2011. PUBLISHED MARCH 2011.

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Expert therapy area review of the key market players and deals highlights for leading areas of industry investment and development. These insightful reviews are based on the strategic data and insights from Thomson Reuters Pharma™ and Thomson Reuters Forecast™.

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PHARMA MATTERS | SPOTLIGHT ON... ANTI-THROMBOTICS

ABSTRACTThe thrombosis market is poised to change dramatically. The possibility of engineering a replacement for warfarin, or a side-effect free oral anticoagulant suitable for chronic thrombosis prevention has presented an attractive opportunity for the pharma industry, and a raft of new products are now entering the market.

A number of hotly anticipated new oral therapies are set to enter the lucrative venous thromboembolism market with the potential to radically change the landscape. The current market has a number of products with acceptable efficacy profile, including low-molecular-weight heparins, warfarin and thrombolytics. However, these products are associated with only moderate safety profiles, and there remains an underlying opportunity to improve outcomes. Promising new drugs such as Xarelto (launched in 2008), Eliquis (under registration) and Pradaxa (launched in 2008) are all oral drugs which are expected to widen the venous thromboembolism (VTE) market significantly, while also extending the prescription period. Additionally, Thomson Reuters Forecast indicates these new-generation drugs are set to undermine Lovenox’s current monopoly in the market.

In the arterial thrombosis setting, Effient and Brilinta have both demonstrated superior effectiveness over the entrenched market leader Plavix. Thomson Reuters Forecast indicates that Brilinta will emerge as the new branded market leader in the longer term based on superiority to Plavix and an equivalent safety profile. Thrombin receptor antagonists, including Merck & Co’s vorapaxar also have significant potential, although bleeding risk remains to be clarified.



SECTION I

INTRODUCTIONThrombosis is a widespread condition and a leading cause of death worldwide, despite the availability of medications to treat and prevent the condition. Deficiencies in existing therapies in terms of efficacy and safety represent a significant revenue opportunity for pharmaceutical companies, and with increasing rates and incidence of disease, it remains a very significant area of unmet clinical need.

To a large extent, conventional management of thrombotic disorders still relies on heparin, warfarin and aspirin, which have been the foundation of anticoagulation treatment for decades, despite significant disadvantages in the outpatient setting as well as for long-term use. In addition to these mainstay treatment options, the VTE market relies heavily on the low-molecular weight heparins such as Lovenox, while the platelet inhibitor Plavix dominates the treatment of arterial-associated thrombosis.

However, the market has witnessed a new wave of activity in recent years, with the introduction of new oral anticoagulants, as well as new competition to rival Plavix. Consequently, the market is expected to rapidly diversify following the penetration of these new agents. This range of new therapies is also likely to balance out generic erosion of the current top-sellers. While most drugs currently available for the treatment of thrombosis and associated disorders need to be administered soon after the onset of symptoms, market winners amongst this new wave of therapies will be easier-to-use prevention products that can be administered more safely over a longer time frame.

The anti-thrombotics market, comprising anticoagulants, heparins and antiplatelet sectors, grew steadily over the period of 2004 to 2009, from $10 billion to $16.8 billion. This growth was not driven by the raft of recent launches, as Lovenox, Plavix and warfarin still collectively occupied 84% of the 2009 market by value. Furthermore, this dominance will come to an end in the near term, with Lovenox generics having entered in mid-2010 and Plavix patent expiry in May 2012. As more new market entrants launch, the number of blockbusters in the market will increase from two to seven, but their collective sales will decline over the 2009 to 2015 period, from $14.4 billion to approximately $12.7 billion, according to Thomson Reuters Forecast. Accordingly, Thomson Reuters Forecast indicates the market as a whole has already peaked once, at just over $16 billion in 2010, but following a decline is expected to peak again in 2015 at $17.6 billion as the new market entrants gain traction.

THROMBOSISA thrombus is an aggregation of platelets within the lumen of a blood vessel. Thrombosis is caused by abnormalities in one or more of three broad categories: blood composition, endothelial cell function, and blood flow, and the formation of a thrombus usually stems from pathogenesis resulting from injury to a vessel wall, stasis of blood flow, or a blood state of hypercoagulability. The clotting system has many balances to ensure that clot formation is appropriate, but abnormal clot formation eventually results in ischemia and potentially infarction.

There are two distinct forms of thrombosis: that which occurs in the venous system and that which occurs in the arterial system. The underlying causes are usually different; arterial clots are associated with atheromatous plaque formation and present as ischemic diseases including acute coronary syndrome (ACS), stroke, myocardial infarction (MI), and peripheral arterial

Aspirin is the gold standard for the antiplatelet primary prevention market, given its effectiveness and low cost.

Until recently, Plavix had no competition; it was the only inhibitor of ADP-induced platelet aggregation on the market until the launch of Effient in 2009.


disease (PAD). Cardiovascular procedures, such as stenting, also irritate the arterial vasculature and can lead to clot formation. Deep vein thrombosis (DVT) and pulmonary embolism (PE) are the major conditions arising from thrombosis in the venous system, which usually results from a simple slowing of blood flow due to major surgery or post-operative immobility. Atrial fibrillation (AF), which has high risk of stroke because of stasis of blood flow in the atria, is also treated similarly to venous thromboembolic disease.

Most disorders associated with thrombosis are initially treated in the hospital or acute setting, which is then followed by patients requiring long-term chronic anti-thrombotic therapy. Arterial and venous thromboses are currently managed differently, with antiplatelet agents showing most benefit in arterial thrombosis, while anticoagulation agents are used for the management of venous disease, although this paradigm may change in the longer term.

ARTERIAL THROMBOSISDue to the platelet’s role in the clotting process, it continues to be a key target for the treatment of arterial-associated thrombosis. Antiplatelet drugs can work in different ways, but they all alter platelet activation at the site of vascular damage, crucial to the development of arterial thromboses; activated platelets undergo shape change, aggregate, and adhere to endothelial cell walls. Inhibition of any of these mechanisms thereby prevents formation of the thrombus.

Platelet inhibitors can be classified according to their mechanism of action; current drug classes include adenosine diphosphate (ADP) antagonists, thromboxane A2 (TXA2) inhibitors, glycoprotein IIb/IIIa (GPIIb/IIIa) antagonists, and direct thrombin inhibitors.

The only member of the TXA2 class is aspirin, which irreversibly inhibits both isoforms of COX and blocks the formation of TXA2 that causes platelet aggregation inhibition. GPIIb/IIIa antibodies and antagonists inhibit the final common pathway of platelet aggregation - cross bridging of platelets by fibrinogen binding to the GPIIb/IIIa receptor. ADP inhibitors block the platelet-bound ADP receptor P2Y12, either reversibly or irreversibly, inhibiting activation of the ADP-mediated GPIIb/IIIa complex and preventing the platelets from changing shape. Direct thrombin inhibitors block thrombin receptor protease-activated receptor-1, thus inhibiting platelet aggregation.

PLAVIx: THE DECLINING PATRIARCHBristol-Myers Squibb (BMS) and sanofi-aventis’s ADP inhibitor Plavix has been a huge success worldwide, with a broad label and strong data from four major clinical trials resulting in Class I recommendations in many guidelines for ACS, PAD and stroke. In ACS, over 95% of stented patients are discharged on Plavix, and data from the CURE trial demonstrated that treatment with Plavix reduced the risk of MI, stroke or cardiovascular death by 20%.

Driven by such strong data and following many years of physician familiarity, the drug became the second biggest selling medicine globally, behind Lipitor, and posted revenue of $9.5 billion in 2010. Sales are expected to stabilize in the short term, according to Thomson Reuters Forecast, remaining at $9.4 billion until 2011, as the incidence of disease where Plavix is indicated continues to rise and competition remains limited.

However, Plavix is facing several headwinds. These include patent expiry in May 2012, with numerous generics companies waiting in the wings. In addition, the drug faces growing competition from new rival ADP receptor inhibitors


including Eli Lilly’s Effient (approved in 2009), as well as new competition from a potentially stronger competitor, AstraZeneca’s Brilinta. Additionally, there are no new major extension trials underway, while data from the CURRENT/OASIS-7 trial examining higher Plavix dosing were also mixed and are not likely to lead to increased revenue. Thomson Reuters Forecast Consensus sales indicate that there will be a significant drop upon patent expiry in 2012 to $5.8 billion, and continue to tail off to $2.3 billion in 2015.

EFFIENT: SLOW UPTAkE, MAY NOT BE SUFFICIENTLY DIFFERENTIATED Eli Lilly and Daiichi Sankyo’s Effient was approved in July 2009 in the US with a competitive label in the ACS- percutaneous coronary intervention (PCI) market. The drug was launched at a premium to Plavix, which Eli Lilly stated is supported by data from a substudy of the TRITON-TIMI trial that demonstrated reduced medical costs relative to Plavix. However, the FDA did not allow a superiority claim relative to Plavix in the label.

The drug’s approval was based on the 13,000-patient TRITON-TIMI38 trial, which conclusively demonstrated superiority over Plavix in PCI, although there was increased bleeding in certain subgroups. Effient was superior to Plavix in its primary endpoint of prevention of MI, stroke and cardiovascular death. However, in the individual components of the primary composite endpoint, only the reduction in non-fatal MI was significant, with positive trends seen in the reduction of cardiovascular death and non-fatal stroke endpoints.

The fatal bleeds seen in the trial were a concern (21 for Effient versus 5 for Plavix); a benefit in cardiovascular mortality would have supported a stronger risk-benefit profile given the increased risk of life-threatening bleeds observed. Bleeding will likely be a significant hurdle to overcome, and the drug is hampered by strict warnings on bleeding risk which are also likely to limit uptake outside the PCI indication, pending additional data. Furthermore, Plavix does not have a bolded warning against use in patients with prior stroke, whereas Effient does. Accordingly, the drug has endured a relatively slow start, posting sales of $115 million in 2010.

The drug also faces other headwinds and is likely to have only 2 years to establish itself in the PCI setting before further competition comes online with Brilinta, with the entry of generic Plavix another significant threat a year later. However, the drug’s potency, as well as its once-daily dosing, should garner use in patients who require more potent therapy; critical to market share will be data from the ongoing TRILOGY study, which is designed to demonstrate superiority over Plavix in medically managed ACS patients. Data are expected in October 2011 and will be key to expanding Effient’s addressable market. Thomson Reuters Forecast’s Consensus sales rise to $734.5 million in 2015.

BRILINTA: A LESS POTENT BUT STRONGER COMPETITORBy contrast, AstraZeneca’s Brilinta has not shown an increased bleeding risk. Data from the PLATO study presented in 2009 demonstrated that Brilinta prevents cardiovascular events more effectively than Plavix. There was an overall 16% relative risk reduction in cardiovascular events for Brilinta over Plavix, with an 18% relative risk reduction in cardiovascular death, a 20% relative risk reduction in MI, a 38% relative risk reduction in stent thrombosis, and a 19% relative risk reduction in total mortality.

These potency data were less impressive than Effient, with a lower event reduction in the primary endpoint (superiority to Plavix in the composite endpoint) and in stent thrombosis. Importantly, however, the bleeding

Brilinta shows superior effectiveness over Plavix, according to data from the PLATO study which showed a 16% relative risk reduction in cardiovascular events for Brilinta over Plavix.


profile was in line with Plavix, which should provide the differentiation to make Brilinta a commercial hit. Furthermore, Brilinta’s reversibility will also allow treatment discontinuation 2 days before coronary artery bypass graft (CABG) and major surgeries (versus 5 to 7 days for Plavix and Effient). On the downside, recommended dosing is twice-daily, while Plavix and Effient are once-daily.

Despite these strong data, the drug has run into delays. The FDA issued an approvable letter in December 2010 following an analysis from a North American subgroup, which indicated a lack of benefit in 9% of patients, raising questions about a possible interaction between Brilinta and high-dose aspirin, commonly used in the US. AstraZeneca carried out further data analyses, and concluded that an interaction was likely. The FDA issued a Complete Response letter in January 2011, and will make its final decision in July 2011.

Positive label negotiations will be crucial for AstraZeneca as differentiating the drug from Plavix will be key once generics come in. Thomson Reuters Forecast Consensus sales indicate that Brilinta will become the leading brand antiplatelet agent over the long term, with sales of $1.4 billion in 2015. However, the entry of generic Plavix in 2012 will significantly temper sales.

REPORTED AND CONSENSUS FORECAST REVENUE (MILLION US$)

GLYCOPROTEIN IIB/IIIA INHIBITORS: USE IN THE SHORT-TERM SETTING ONLYThe GPIIb/IIIa inhibitors are a class of antiplatelet agents that are frequently used during PCI. Their use has fallen dramatically since the introduction of Plavix, particularly as they were initially licensed based on clinical trials using unfractionated heparin as the anticoagulant of choice. However, they still find a place in the short-term use market, particularly in patients where ischemic risk is high.

Merck & Co’s Integrilin is the market leader in the GPIIb/IIIa sector, with 56% of total sales in 2009. The drug is expected to maintain market share, bolstered by solid clinical data from the ESPRIT trial, which demonstrated a 37% relative risk reduction for MI in patients undergoing stenting, and a favorable cost profile. The company carried out the EARLY-ACS trial, which investigated early use of Integrilin in high-risk ACS patients as soon as they are diagnosed. However, the trial missed all endpoints and without this indication sales are likely to continue to decline relative to the ADP inhibitor blockbusters, which in addition, are orally dosed and can be used in the longer-term. Thomson Reuters Forecast Consensus sales indicate that 2015 sales will be minor compared to the market leaders, with sales of $200 million at that time.

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Thomson Reuters Forecast also indicates declining sales for Eli Lilly and Johnson & Johnson’s GPIIb/IIIa inhibitor ReoPro, having been clipped for many years by positive data for Integrilin from the ESPRIT trial. Attempts to support sales by extending usage into stroke patients failed after safety concerns following increased rates of intracranial hemorrhage in the AbESTT-II trial. Medicure’s GPIIb/IIIa inhibitor Aggrastat will likely remain a third-line option.


FURTHER ALONG THE ANTIPLATELET PIPELINEUntil recently, The Medicine Co (TMC)’s cangrelor, the first injectable reversible ADP inhibitor, was in phase III development for the prevention of arterial thrombosis in patients undergoing PCI. Unlike Plavix and Effient, platelet activity resumes after 60 minutes, which was expected to allow flexibility should patients require CABG. However, development in ACS was discontinued as non-inferiority to Plavix was not observed in the company’s CHAMPION trials. The company decided instead to focus on cangrelor as a short-term therapy to allow safe ‘bridging’ of patients during the pre- and post-surgical periods where patients discontinue Plavix and are at increased risk. The company believes that the rapid onset, offset and titratable pharmacology make cangrelor a good candidate for this potential short-term use.

Competition for Plavix from outside the ADP inhibitor class is also anticipated. Potentially the most promising is Merck & Co’s vorapaxar, which blocks thrombin receptor protease-activated receptor-1 thereby inhibiting platelet aggregation. However, the drug has suffered a recent setback with the termination of one of two pivotal phase III trials (TRACER) in ACS due to increased rates of bleeding. Another phase III trial, TRA 2P, investigating the drug in the secondary prevention of cardiac events post-ACS will continue, but treatment of patients included in the trial with previous stroke has been terminated.

Despite this setback, vorapaxar is still being tested in 20,000 patients. Vorapaxar’s promise was that it was conceivable that it might not cause extra bleeding when coadministered with Plavix, which is now being called into question. How valuable this new treatment is will depend on exactly how much bleeding risk there is. Thomson Reuters Forecast Consensus sales currently predicts blockbuster status by 2015, with expected sales of $1.3 billion.

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Vorapaxar is a first-in-class thrombin receptor antagonist.


VENOUS THROMBOSISVenous thromboembolism (VTE) is the collective term for DVT and PE, and the most at-risk patients are those who have undergone orthopedic surgery, notably hip or knee replacement. AF, which causes clots because of stasis of blood flow in the atria, is also considered a venous thrombotic disease.

The current market landscape for VTE is competitive, and there are more than ten approved products for VTE, which include anticoagulants and thrombolytics. The market is largely dominated by generic products; although there are few branded products, competition between the generic and branded products is strong. In terms of efficacy, the currently marketed products are effective in reducing total VTE events, reducing proximal DVT events and decreasing the risk of PE; however, they are associated with serious side effects, such as increased bleeding and thrombocytopenia. Thus the need for new targeted therapies with improved efficacy and safety profiles remains.

Low molecular weight heparins entered the market in the mid-1990s, and became the mainstay of DVT treatment given clinical advantages including dose predictability, less bleeding and no thrombocytopenia. However, the dominance that low-molecular-weight heparins have held in the VTE market will be severely reduced over the next decade following the introduction and market penetration of several novel oral agents. These oral agents will offer significant advantages over this class of drugs, most notably, Bayer’s Xarelto, BMS and Pfizer’s Eliquis and Boehringer Ingelheim’s Pradaxa, none of which require patient monitoring. These new agents have all targeted DVT prophylaxis as the quickest path to market, but the oral products will not present much advantage in the acute setting, with the largest opportunity residing in AF, medically managed ACS, and secondary prevention of VTE.

Further growth in the market will be supported by the high incidence of the disease, increased uptake of novel drug classes and the expected launch of me-too candidates with improved efficacy and safety.

LOVENOx: THE BROADEST LABELThe dominant low molecular weight heparin is sanofi-aventis’s Lovenox, with the broadest label and largest clinical trial database. With limited competition, sales reached $4 billion in 2009, declining slightly in 2010 to $3.9 billion. Lovenox is indicated for the prevention of post-surgical DVT, the prevention of DVT in medical patients, treatment of DVT with or without PE, prevention of morbidity and mortality subsequent to unstable angina with non-Q wave MI, and treatment of STEMI patients receiving thrombolysis and being managed medically or with PCI. Numerous trials have demonstrated the superiority of Lovenox over unfractionated heparin in each of these settings, including Synergy, ExTRACT-TIMI25, Prevail and ExClaim.

Despite the strong clinical profile, the drug is facing numerous challenges. Sales are being affected by the launch of a generic version of the drug in mid-2010, following several attempts from sanofi-aventis to prevent the FDA from approving a generic version based on the drug’s macromolecular nature. In addition, further generics are expected in the EU as well as the US, despite high regulatory hurdles for approving generic versions of this complex molecule. However, potential competition from novel oral agents, such as Pradaxa and Xarelto, could pose the biggest threat to the heparins franchise. Thomson Reuters Forecast Consensus sales indicate a decline steadily over the longer term, dipping to $2.1 billion in 2015.


ARIxTRA: OPPORTUNITY MISSEDGlaxoSmithKline (GSK)’s Arixtra, a pentasaccharide inhibitor of activated Factor Xa, entered the market in 2002. However, the drug failed to be a significant competitor to Lovenox as its label in the US is restricted to prophylaxis of DVT, and gains versus low molecular weight heparins have been modest, likely due to a slight increase of bleeding seen in orthopedic prophylaxis trials.

The company’s efforts to extend the label to include prophylaxis in patients with ACS seem to have been halted by two approvable letters in 2007, with no further updates since that time. Trial data in ACS were positive, with equivalent efficacy to Lovenox but fewer bleeds seen in the OASIS-5 trial, and an opportunity for a competitive market position against Lovenox may have been lost. Arixtra sales in 2010 were a mere 13% of the revenue posted by Lovenox, and although Thomson Reuters Forecast expects Consensus sales to rise by 2015, which is in contrast to those of Lovenox, Consensus 2015 sales of $600.1 million will mean the drug remains a minor player in the market.

LOVENOX AND ARIXTRA: TOP SELLING VENOUS THROMBOSIS DRUGS REVENUE (MILLION US$)

xARELTO: BROAD DEVELOPMENT STRATEGY BUT IS THERE A LIVER SIGNAL?Competition for Lovenox from outside the heparins class has been expected for many years but is only now materializing. AstraZeneca’s direct thrombin inhibitor Exanta had been expected to revolutionize the oral anticoagulants market but, following approval in DVT prophylaxis, was withdrawn in 2006 due to liver toxicity. Boehringer Ingelheim’s direct thrombin inhibitor Pradaxa was the first oral anticoagulant to reach the market following the Exanta disappointment, but it is Bayer’s Xarelto that may hold the greatest promise.

Xarelto is a Factor X inhibitor, a class of anticoagulants that act directly on Factor X in the coagulation cascade without using antithrombin as a mediator. It is Xarelto’s broad development strategy across multiple VTE indications that is likely to be key to its future success. Xarelto launched in Europe in 2008 for the initial indication of prevention of VTE in patients undergoing orthopedic surgery. This approval was based on data from the RECORD-1, -2 and -3 studies, which examined Xarelto versus Lovenox, consistently demonstrating superiority in efficacy endpoints, with a similar bleeding profile. However, the FDA noted concerns of hepatotoxicity and issued an approvable letter pending further analysis of safety data from ongoing trials. A Complete Response was submitted in January 2011.

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Bayer is looking to broaden Xarelto’s label in several other potentially more meaningful acute and chronic indications, with trials undertaken including MAGELLAN for VTE prevention in medically ill patients, EINSTEIN in VTE treatment and secondary prevention, and ROCKET AF for AF prevention. These new indications will greatly expand the drug’s reach and revenue potential, and are also likely to enable full characterization of the hepatotoxicity risk. Data from the longer-term phase II study ATLAS ACS TIMI46 may also alleviate toxicity concerns as the trial is studying a higher dose over a longer time period. Thomson Reuters Forecast’s Consensus sales build steadily, reaching $2.3 billion in 2015.

PRADAxA: POTENTIAL SEA CHANGE IN AFBoehringer Ingelheim’s Pradaxa, an oral direct thrombin inhibitor, was the first competitor to Lovenox to reach the US market across all classes, and the first new oral anticoagulant to reach the US market for 50 years. It was approved in the EU for the prevention of DVT following orthopedic surgery in 2008, and in January 2011, it stole a march on its competitors with approval in the US for the prevention of stroke in patients with AF.

Data from the phase III RE-NOVATE and RE-MODEL trials supported approval for DVT, which demonstrated non-inferiority to Lovenox in hip replacement surgery; rates of bleeding were similar. The phase III program for stroke prevention in AF involved RE-LY, the largest AF trial to date, for which data were reported in 2009. Data were impressive, with two different doses of Pradaxa over 2 years demonstrating comparable-to-better efficacy in preventing stroke and equal-to-lower risk of bleeding versus warfarin. The highest dose demonstrated a 34% reduction in the incidence of stroke. There were some issues surrounding the trial design for RE-LY, primarily as it was open-label. However, the quality of the data are likely to outweigh any concerns, and Thomson Reuters Forecast expects the drug to see rapid uptake in prevention of stroke in AF, despite the FDA not allowing a superiority claim over warfarin in the label.

The drug also faces limited competition among current injectable direct thrombin inhibitors, including TMC’s Angiomax and Mitsubishi Tanabe’s argatroban, which according to Thomson Reuters Forecast do not pose a significant threat. Angiomax failed to get approval for medically managed ACS and is now likely confined to PCI.

OVERCOMING LOVENOx: THE HURDLES FACED Much of the success of Pradaxa and Xarelto will depend on how they can penetrate the existing market and then expand its current scope. There are a number of factors that could constrain their uptake. However, both drugs are expected to be able to assert themselves in the market, and the sales potential of Pradaxa and Xarelto remains strong.

All anti-clotting agents carry a risk of unwanted bleeding events, and the new oral anticoagulants are no exception. Importantly, the effects of many of the older anti-thrombotic agents can be reversed if a patient is bleeding, whereas currently Pradaxa and Xarelto cannot be reversed quickly. Price could be another hurdle, as both are expensive and some payers are likely to opt for the less expensive options. Generic Lovenox will also create pricing pressures here and will potentially lower prices across the sector.

Uptake in the VTE primary prophylaxis market may also be slow as this is characterized by shorter periods of hospital-based therapy, where delivering injectable agents, such as Lovenox, is not a significant disadvantage. However, the stroke prevention in AF and prevention of recurrent VTE indications is where the blockbuster sales will lie, and rapid uptake and deep penetration of these drugs is expected in these markets.



FURTHER ALONG THE PIPELINEPradaxa and Xarelto potentially face considerable longer-term competition from other rivals currently in development. Published in 2010, findings from the ADVANCE-2 study show Pfizer and BMS’s Eliquis, a highly selective Factor Xa inhibitor, is more effective than Lovenox in preventing VTE after knee replacement surgery and not associated with increased bleeding. The drug was filed for DVT prevention following orthopedic surgery in Europe in March 2010, and a rolling NDA was initiated in the US for the prevention of stroke in AF in October 2010. The AVERROES phase III data in stroke prevention has validated both the efficacy and safety profile in this setting, and could offer some positive points of differentiation versus Pradaxa. However, use in patients who have had an MI will not be pursued following an increased bleeding risk seen in the APPRAISE-2 trial. Thomson Reuters Forecast Consensus sales indicate apixaban will begin slowly, but it is forecast to reach $1.6 billion in 2015.

Another novel oral Factor Xa inhibitor under development is Portola’s betrixaban. In addition to positive data in VTE prevention trials in knee replacement surgery and stroke prevention in AF, betrixaban is the only novel oral anti-clotting agent being tested in patients with renal malfunction.

The Factor Xa inhibitor edoxaban from Daiichi Sankyo is also targeting approval in AF. The phase III ENGAGE AF-TIMI 48 trial is comparing edoxaban with warfarin for the prevention of stroke and systemic embolism in around 20,000 patients with AF and has completed recruitment. Development for the treatment of VTE is also ongoing, though the drug will only be filed for the prevention of VTE in orthopedic surgery in Japan. Accordingly, Consensus sales reported by Thomson Reuters Forecast remain low, at $140 million in 2015.

In contrast, competition to Lovenox from within the low molecular weight heparin class has largely failed, with development of the most advanced competitor, sanofi-aventis’s semuloparin, narrowed down to only include oncology and DVT prophylaxis in abdominal surgery. Development in general medical conditions and orthopedic surgery DVT prophylaxis was discontinued; Thomson Reuters Forecast indicates Consensus sales of $283.3 million in 2015.

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SECTION II

DEALS HIGHLIGHTSAnti-thrombotic therapeutics belong to a broad class of drugs that include antiplatelet agents, anticoagulants and thrombolytics, targeting a variety of therapy areas across arterial and venous thromboembolism indications. Deals coverage on Thomson Reuters Pharma indicates that approximately 250 deals have been forged under the ‘thrombosis’ category, some dating back to the late 1980s.

The following deals cover some prolific players in the development of promising anti-thrombotic agents, including sanofi-aventis, Daiichi Sankyo and Merck & Co. This selection of notable and high-valued agreements may provide some partnering insight into this vast therapeutic market.

SANOFI-AVENTIS: AN ExTENSIVE ANTI-THROMBOTIC PARTNERING LANDSCAPEIt is apparent that sanofi-aventis has emerged as a significant player in the anti-thrombotics arena. The company’s involvement in the field dates back to its earlier incarnation, Sanofi-Synthelabo.

Plavix, an inhibitor of ADP-induced platelet aggregation, was codeveloped and launched by Sanofi-Synthelabo and BMS. Sanofi-Synthelabo partnered with BMS in 1993, whereby BMS acquired worldwide codevelopment and comarketing rights outside Japan. Specific financial terms were not disclosed. The deal is set to expire in 2013 or with the expiration of all patents and exclusivity rights in the individual territories.

Sanofi-Synthelabo granted Japanese rights to Daiichi Seiyaku by October 1994; financial terms for this deal were also undisclosed. In September 2005, the holding company Daiichi Sankyo was formed following the merger of Daiichi Seiyaku and Sankyo. As a result, Daiichi Sankyo returned Plavix rights to sanofi-aventis, as the merger included Sankyo’s potential rival Effient; Daiichi Sankyo would continue to copromote Plavix until Effient’s launch. In February 2007, the joint promotion agreement was terminated, ending Daiichi Sankyo’s involvement with Plavix. Sanofi-aventis proceeded to launch the drug alone in Japan in May 2009.

In addition to arterial thrombotics such as Plavix, sanofi-aventis has also been involved in the development of a number of venous thrombotics.

“We look forward to the opportunity to work with Bristol-Myers Squibb to bring this important new compound to patients around the world. We believe that Plavix represents an important advance in treatment for a broad group of patients at risk of heart attack, stroke, and peripheral arterial disease.” Kurt Briner, president of Sanofi pharma and executive Vice president of sanofi-aventis

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Lovenox, a low-molecular-weight fraction of heparin, was developed and launched by Rhone-Poulenc Rorer, which became sanofi-aventis following Rhone-Poulenc’s merger with Hoechst in December 1999. In June 2010, Kaken and sanofi-aventis concluded a sales and marketing agreement for the anticoagulant. Kaken agreed to promote, disseminate and collect information related to safety, as well as taking on marketing responsibilities in Japan from October that year; sanofi-aventis was to remain the marketing authorization holder. The company expected to utilize its human resources more efficiently by outsourcing the drug’s marketing to Kaken. Financial terms for the deal were not disclosed.

Arixtra, a synthetic pentasaccharide inhibitor of activated Factor Xa, was originally developed and launched by Sanofi-Synthelabo in collaboration with NV Organon (now Organon BioSciences). The product is now marketed by GSK.

A collaborative agreement between Sanofi-Synthelabo and Organon for the development of Arixtra was signed by July 1995. Joint ventures, equally owned by the companies, would be responsible for distribution and commercialization in the US, Canada and Mexico, while Sanofi-Synthelabo remained solely responsible for marketing and commercialization in Europe and the rest of the world, excluding Japan. Specific financial terms of the agreement were undisclosed. In January 2004, it was reported that Sanofi-Synthelabo planned to reacquire Organon’s rights to Arixtra, subject to regulatory approval. By October that year, Organon had discontinued development of the drug and returned all rights to Sanofi-Synthelabo.

Subsequently, in April 2004, Sanofi-Synthelabo reported that it was to divest exclusive rights for Arixtra and an associated manufacturing plant to GSK, contingent on the Sanofi-Synthelabo/Aventis merger. Financial terms of the divestment were undisclosed. Following the successful formation of sanofi-aventis in August 2004, Arixtra’s divestment to GSK was completed in September. The following year, GSK signed a two-year copromotion agreement in the US with Adolor, with GSK to provide cost reimbursement to Adolor. However, the deal was terminated in 2006.

Sanofi-aventis is currently conducting phase III trials on semuloparin, its ultra-low molecular weight heparin, for the potential prophylaxis of venous thromboembolic events in medical and surgical patients. Currently, sanofi-aventis holds worldwide rights and the program remains unpartnered.

DRUGLICENSING COMPANY

PARTNER COMPANY

DEAL START DATE

DEAL VALUE (US $)*

Plavix sanofi-aventis Bristol-Myers Squibb

1993 Undisclosed

Plavix sanofi-aventis Daiichi Sankyo October 1994

Undisclosed

Lovenox Kaken Pharmaceutical

sanofi-aventis June 2010 Undisclosed

Arixtra Sanofi-Synthelabo

NV Organon July 1995 Undisclosed

Arixtra Sanofi-Synthelabo

GlaxoSmithKline April 2004 Undisclosed

argatroban Mitsubishi Sanofi-Synthelabo October 1993

Undisclosed

TABLE 1: SUMMARY OF CERTAIN SANOFI-AVENTIS AGREEMENTS FOR ANTI-THROMBOTICS

* Approximate values based on the achievement of all milestones for the principal components included in the deal.

“Arixtra is an important medical option for the prevention and treatment of deep vein thrombosis and pulmonary embolism. Aligning and integrating the Adolor and GSK sales forces will expand our reach with Arixtra while paving the way for future collaboration in the surgical market.” Kevin Lokay, Vice president of glaxoSmithKline oncology and acute Care


DAIICHI SANkYO: A LICENSING PORTFOLIO WHICH INCLUDES ARGATROBAN, EFFIENT AND EDOxABANDaiichi Sankyo also shares a strong interest in the licensing of promising anti-thrombotic agents. Both Daiichi and Sanofi-Synthelabo (as Synthelabo) inlicensed rights to Mitsubishi’s argatroban, a non-protein, arginine-related thrombin inhibitor, indicated for chronic arterial obstruction, acute cerebral thrombosis and heparin-induced thrombocytopenia.

Synthelabo entered into a codevelopment, sales and marketing agreement with Mitsubishi in Europe and francophone Africa in October 1993. Financial terms of which were undisclosed. However, by February 2000, Sanofi-Synthelabo had dropped argatroban, thus terminating the deal.

By October 1994, Mitsubishi granted Daiichi Japanese sales and comarketing rights to the thrombin inhibitor. Financial terms were not disclosed. Argatroban was launched as Slonnon by Daiichi and as Novastan by Mitsubishi.

Effient, a P2Y12 inhibitor of ADP-induced platelet aggregation, was developed and launched by Daiichi Sankyo (formerly Sankyo) and Eli Lilly. The companies signed a Letter of Intent to develop the drug in December 2000, and agreed to copromote in the US and comarket in the rest of the world, excluding territories where Eli Lilly had exclusive sales and marketing rights. Development responsibility would be shared between the companies, and UBE Industries was designated as the manufacturer of the bulk material. Eli Lilly agreed to pay Sankyo a signing fee, milestone payments and royalties on sales of the product. Daiichi Sankyo agreed to copromote the drug in Mexico with Eli Lilly, under a Eli Lilly affiliate in the region.

Daiichi Sankyo is also currently developing the Factor Xa inhibitor edoxaban as an anticoagulant for the prevention of venous thromboembolic events, including stroke; the company expects approval in 2011. The program is unpartnered, and Daiichi Sankyo hold worldwide rights.


PARTNER COMPANY

DEAL START DATE

DEAL VALUE (US $)*

argatroban Mitsubishi Daiichi Seiyaku October 1994

Undisclosed

Effient Daiichi Sankyo Eli Lilly December 2000

Undisclosed

Effient UBE Industries Sankyo December 2000

Undisclosed

TABLE 2: SUMMARY OF CERTAIN DAIICHI AGREEMENTS FOR ANTI-THROMBOTICS


“This collaboration reinforces our commitment to cardiovascular research and expands our growing portfolio of antithrombotic compounds. We are looking forward to a long and productive relationship with Sankyo, a company widely recognized for its cardiovascular expertise and innovation.” august m Watanabe, mD and executive Vice president of Science and technology for Lilly


MERCk & CO: ESTABLISHED ARTERIAL THROMBOSIS THERAPEUTICS AGREEMENTSMerck & Co has also established its position in the development of arterial thrombosis therapeutics. Following Merck & Co’s merger with Schering-Plough in November 2009, the company is currently developing the oral thrombin receptor antagonist vorapaxar for the secondary prevention of cardiac events in patients with prior MI or PAD. Merck expects to file an NDA in 2011. The program is unpartnered, with Merck & Co holding exclusive worldwide rights.

Merck & Co also holds interests in various AstraZeneca products, including the P2T receptor antagonist Brilinta, under a First-Option Agreement. In March 2010, AstraZeneca notified Merck & Co that it would exercise the First Option related to the relinquishment of Merck & Co’s rights. Brilinta has been launched in the UK and Germany for the prevention of atherothrombotic events in adults with acute coronary syndromes. There are currently no other agreements for the product.

Integrilin, a synthetic cyclic heptapeptide GPIIb/IIIa antagonist and platelet aggregation inhibitor, derived from rattlesnake venom, was codeveloped and launched by Schering-Plough (now Merck & Co) and drug originator COR Therapeutics (now Millennium). The companies entered a worldwide collaborative development and commercialization agreement in April 1995. Under the deal terms, the companies would copromote and share profits in North America, and Schering-Plough retained the right to launch the drug in Europe and assist COR in training a US cardiovascular sales force. COR would receive a $20 million licensing fee, milestone payments of approximately $100 million, and royalties on European sales for a specified period, after which the company could copromote in the territory and share profits. COR received its first milestone payment, worth $24 million, in June 1998, triggered by Integrilin’s approval in the US. Approval in the EU in August 1999 triggered a further $12 million milestone payment. Schering-Plough returned European marketing rights to Millennium in June 2004, retaining ex-European rights (including US copromotion rights). However, by the following year, Schering-Plough had acquired exclusive US development and commercialization rights. Millennium would receive $35.5 million upfront and royalties for the US lifespan of Integrilin (set as $85 million annually for the following 2 years). Millennium would also receive approximately $45 to $50 million for the purchase of existing product inventories.

Other deals for Integrilin include a collaboration between COR, Schering-Plough and Genentech to copromote the drug with tenecteplase and recombinant alteplase in hospitals across the US, signed in January 2001, an exclusive European marketing rights deal with GSK in June 2004, and a manufacturing agreement with Peptisyntha by May 2010.

LICENSING COMPANY

PARTNER COMPANY

DEAL START DATE

DEAL VALUE (US $)*

COR Therapeutics Merck & Co April 1995 ~ $375 million

Genentech COR Therapeutics and Schering-Plough

January 2001 Undisclosed

Millennium Pharmaceuticals

GlaxoSmithKline June 2004 Undisclosed

Peptisyntha Millennium Pharmaceuticals

May 2010 Undisclosed

TABLE 3: SUMMARY OF AGREEMENTS FOR INTEGRILIN


“We are very pleased to have Schering-Plough, with its extensive capabilities and drug development experience, as our worldwide partner for Integrelin. We believe this agreement will help us to realize the full potential of Integrelin and help us build the resources we need in an effective and efficient manner.”Vaughn m Kailian, president and Ceo of Cor therapeutics


Aggrastat, a non-peptide GPIIb/IIIa receptor antagonist, was developed by Merck & Co, and is currently marketed by Medicure in the US and Iroko Pharmaceuticals in ex-US markets. Merck & Co’s Japanese affiliate Banyu has held development and marketing rights in Japan since December 1996.

Initially, Guilford obtained exclusive commercial rights in the US, Puerto Rico, Virgin Islands and Guam from Merck & Co in October 2003. Guilford agreed to pay Merck & Co $84 million, as well as royalty payments based on net sales until December 2012. However, in August 2006, following MGI Pharma’s acquisition of Guilford, Medicure bought the US commercialization rights from MGI Pharma for $19 million. Medicure would also pay Merck & Co certain royalty payments. In January 2010, it was reported that Medicure was seeking partners for outlicensing the product.

Iroko acquired all ex-US commercial rights from Merck & Co in January 2008; deal terms were undisclosed. Since then, Iroko has sublicensed rights to Aspen PharmaCare Australia. Subsequently, Aspen PharmaCare Australia granted Handok rights to market the drug in Korea by August 2009.

LICENSING COMPANY

PARTNER COMPANY

DEAL START DATE

DEAL VALUE (US $)*

Merck & Co Banyu Pharmaceutical

December 1996 Undisclosed

Merck & Co Guilford Pharmaceuticals

October 2003 $84 million (plus royalties)

Merck & Co Iroko Pharmaceuticals

January 2008 Undisclosed

TABLE 4: SUMMARY OF AGREEMENTS FOR AGGRASTAT


BRISTOL-MYERS SqUIBB AND PFIzER ENTER BILLION-DOLLAR DEAL FOR ELIqUISOne of the highest valued anti-thrombotic deals on Thomson Reuters Pharma covered a collaborative agreement between Pfizer and BMS for Eliquis signed in April 2007.

Eliquis, a follow-on compound to BMS’s oral Factor Xa antagonist razaxaban, is a potential anticoagulant in development for a number of thromboembolic indications.

BMS granted Pfizer worldwide rights to codevelop Eliquis for a range of venous and thrombotic conditions. Pfizer agreed to pay $250 million upfront, 60% of the development costs and up to $750 million in milestones. Commercialization expenses and profits would be shared equally between the companies.

“We’re very pleased to collaborate with Bristol-Myers Squibb on the worldwide commercialization of apixaban, which has the potential to be a best- in-class product and would represent an excellent strategic fit with our global cardiovascular franchise. We see significant opportunities for an orally active anticoagulant with the clinical profile apixaban has demonstrated to date, particularly because of the clear need for new treatments to combat thrombosis and stroke.”Jeffrey B Kindler, Chairman and Ceo of pfizer


xARELTO: A PARTNERSHIP BETWEEN ORTHO-MCNEIL AND BAYERXarelto, an oral direct Factor Xa inhibitor indicated for the prevention of venous thromboembolism in adults undergoing elective knee or hip replacement surgery, has been developed and launched by Bayer and its partner Ortho-McNeil.

The companies agreed in October 2005 to jointly develop and market Xarelto worldwide. Ortho-McNeil acquired exclusive marketing rights in the US for the cardiology, primary care and hospital specialty markets, whilst Bayer retained an option to copromote Xarelto in the US hospital and specialty markets. Bayer would also retain sole ex-US marketing rights. As part of the financial terms of the deal, Bayer would receive an upfront payment, milestone payments of up to $290 million and royalties of up to 30%.


PARTNER COMPANY

DEAL START DATE

DEAL VALUE (US $)*

Eliquis Bristol-Myers Squibb

Pfizer April 2007 < $1 billion

Xarelto Bayer Ortho-McNeil Pharmaceutical

October 2005

< $290 million + royalties

TABLE 5: NOTABLE HIGH-VALUE DEALS FOR ANTI-THROMBOTICS


CONCLUSIONAs expected, pharma giants such as sanofi-aventis, Daiichi Sankyo and Merck & Co feature prominently in the development of some of the most significant and promising anti-thrombotic therapeutics. The continued presence of established companies like GSK, AstraZeneca, BMS and Eli Lilly further illustrates the importance of the field and any potential interest for investment. However, it is worth noting that the portfolio of established and promising anti-thrombotics covered by Thomson Reuters Forecast involve little or no partnering activity, eg Merck & Co’s vorapaxar, sanofi-aventis’s semuloparin, Daiichi Sankyo’s edoxaban and Boehringer Ingelheim’s Pradaxa, potentially representing an opportunity for partnering activity. Other proprietary agents have started to emerge, which may also dramatically affect the deals landscape of well-established products currently on the market.

Notably, Portola (the US spin-off company from Millennium) forged two noteworthy deals in 2009, each worth approximately $0.5 billion. The deals covered three anti-thrombotic agents, all currently in phase II development. In February 2009, the company granted Novartis exclusive worldwide rights to develop and commercialize iv and oral formulations of the platelet aggregation inhibitor elinogrel, as part of a deal worth up to $575 million plus royalties. Later in July, the company granted Merck & Co worldwide rights to develop and commercialize Factor Xa inhibitor betrixaban, under a deal worth up to $470 million plus royalties. Such deals may support wide-ranging transition in the market as it continues to progress and diversify.

“The collaboration with Bayer HealthCare strengthens our growing cardiovascular franchise. We share a common vision with Bayer and look forward to contributing to the successful development of this promising compound by capitalizing on our clinical and commercial expertise in the area of thrombosis.” Joe Scodari, Worldwide Chairman of pharmaceuticals group at Johnson & Johnson


Vast potential exists for novel anticoagulant and antiplatelet agents despite considerable overlaps between patient populations. The heparins and Plavix form the mainstay of arterial thrombosis management; these act through different mechanisms, but both suffer from a predisposition to increased bleeding. New competition is now entering the market that will rival Plavix’s market domination in arterial thrombosis, most notably Brilinta and Effient, which have shown superiority over Plavix. Brilinta is the stronger competitor, with comparable rates of bleeding as Plavix; AstraZeneca will be keen to negotiate superiority over Plavix into the label to ensure it can defend its market position when Plavix generics enter in 2012.

In terms of the venous market, Exanta was the first oral anticoagulant in 50 years and expected to revolutionize the market and steal market share from the existing market leader Lovenox. However, the drug resulted in post-approval liver toxicity, and subsequently withdrawn. New oral competition is now arising from Xarelto and Pradaxa, which have both shown promise in trials of the most lucrative long-term stroke prevention in AF indication.

Overall, the safety hurdles in the anti-thrombotics sector remains high, and new agents will have to demonstrate superior effectiveness that outweighs any increased bleeding risk. Furthermore, new agents will require outcomes data for full market penetration. However, paradigm shifts towards long-term secondary prevention in both the arterial and venous thrombosis markets, as well as oral prophylaxis in the venous category, mean that both markets are poised to change dramatically to finally achieve that most elusive of goals, the complete replacement of warfarin.


NOTES

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Spotlight On... Anti-Thrombotics, A Review of Jan-Mar 2011-- Pharma Matters Report