Antithrombotic drugs market

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N E W S & A N A LY S I S

FROM THE ANALYSTS COUCH

Kritika Chaudhari, Bashar Hamad and Basharut A. Syed Image from COBALT7 IMAGING/Alamy

Cardiovascular diseases (CVDs) are the single largest killer worldwide, accounting for ~7.5million deaths each year. The death tollis estimated to reach 25 million by 2030 (see the World Health Organization CVD http://www.who.int/mediacentre/factsheets/fs317/en/

Web End =factsheet http://www.who.int/mediacentre/factsheets/fs317/en/

Web End =N317 ). Thrombotic (arterial and venous) events are a major complication of CVD and can be fatal if not appropriately managed.

Current therapeutic options

Antithrombotic drugs are categorized into three broad types: platelet aggregation inhibitors (PAIs), fibrinolytics and anticoagulants.

PAIs prevent blood clots by blocking one of the platelet surface receptors and are mainly used for long-term management of arterial thrombosis. Fibrinolytics allow reperfusion by converting plasminogen to plasmin and dissolving fibrin. These drugs, used for lysing an already formed thrombus, are most effective when administered within 46hours of a cardiovascular event.

Anticoagulants, used as short- and long-term options for both arterial and venous thrombi, comprise heparins,

vitaminK antagonists (VKAs), direct thrombin inhibitors (DTIs) and direct factorXa (FXa) inhibitors. Heparin inactivates thrombin and FXa through an antithrombin-dependent mechanism. Low-molecular-weight heparins (LMWHs) are the major type of heparin. By contrast, DTIs act independently of antithrombin and bind directly to either soluble or fibrin-bound thrombin. VKAs, with warfarin being the most commonly used drug, competitively inhibit vitaminK epoxide reductase (VKOR). Despite being popular, this drug class suffers from serious drawbacks, such as drugfood interactions, and requires close monitoring of drug levels in the blood.

Direct FXa inhibitors are the newest category of anticoagulants. They interfere with the binding ability of FXa in an antithrombin- independent manner. Advantages of oral anticoagulants (OACs) such as DTIs and direct FXa inhibitors include easy dosing regimens and no fooddrug interactions, thereby eliminating the need for constant patient monitoring. Despite the availability

of a wide range of drugs for thromboembolic disorders, demand persists for novel therapies that can demonstrate superior benefits compared with existing options.

Pipeline analysis

Several promising therapies, particularly targeting the warfarin replacement market, are in development (TABLE1). Cangrelor (The Medicines Company) is a P2Y purinergic receptor 12 (P2Y12) antagonist being developed for CVD. As a fast-acting inhibitor of platelet aggregation that is excreted out of the system within 1 hour, cangrelor demonstrated a reduced risk of bleeding compared to clopidogrel in the PhaseIII PHOENIX trial. However, in February 2014,a US Food and Drug Administration (FDA) advisory panel disapproved cangrelor, citing flaws in the clinical trial design.

Vorapaxar (Zontivity; Merck & Co.), a once-daily proteinase-activated receptor1 (PAR1) antagonist, is in clinical trials forthe secondary prevention of heart attacksin patients with no history of stroke and transient ischaemic attacks (TIAs). Despite early termination of two PhaseIII trials TRACER and TRA 2P-TIMI 50 owing to excessive intracranial haemorrhage, vorapaxar was notably well tolerated by patients, and in May 2014 the FDA approved the drug for this setting.

EP217609 (Endotis Pharma) combines dual mechanisms of action with FXa (indirect) and FIIa (direct) inhibition.

The injectable synthetic agent is in PhaseIIa trials in patients undergoing open heart surgery, with potential use in patients with acute coronary syndrome (ACS) who underwent percutaneous coronary interventions (PCIs). It is neutralizable within minutes with avidin an antidote being developed in parallelby Endotis. This makes EP217609 a more predictable option than current standards of care to manage bleeding risks.

Betrixaban (Portola Pharmaceuticals) is being investigated as a novel direct

FXa inhibitor that, unlike the approved FXa inhibitors, is not metabolized by cytochrome P450 3A4 (CYP3A4), which reduces therisk of drugdrug interactions. Data from PhaseII trials showed that betrixabanhad similar efficacy and safety to the

Table 1 | Current status of selected antithrombotics in development

Drug Developers Class Formulation Indication Status

Vorapaxar Merck & Co. PAR1 inhibitor

Oral Post-ACS Approved May 2014

Cangrelor The Medicines Company

P2Y12 inhibitor Injectable ACS/PCI Filed

Desmoteplase Lundbeck tPA Injectable Ischaemic stroke

Filed

Betrixaban Portola Pharmaceuticals

FXa inhibitor Oral VTE PhaseIII

Tecarfarin Armetheon VKOR Oral Prosthetic heart valves

PhaseIII

REG1 Regado FIXa inhibitor Injectable PCI PhaseIII

EP217609 Endotis FXa/FIIa inhibitor

Injectable ACS/cardiac surgery

PhaseII

THR-18 D-Pharm tPA Injectable Ischaemic stroke

PhaseII

TeaRxaban TeaRx/Roche FIXa inhibitor Oral VTE PhaseII

Andexanet alfa

Portola Pharmaceuticals

FXa antidote Injectable Major bleeding

PhaseIII

ACS, acute coronary syndrome; FIIa/FIXa/FXa, factor IIa/IXa/Xa; P2Y12, P2Y purinergic receptor 12; PAR1, proteinase-activated receptor 1; PCI, percutaneous coronary intervention; tPA, tissue-type plasminogen activator; VKOR, vitaminK epoxide reductase; VTE, venous thromboembolism.

N E W S & A N A LY S I S

FROM THE ANALYSTS COUCH

LMWH enoxaparin. A global PhaseIIItrial initiated in March 2012 is evaluating betrixaban in high-risk patients with venous thromboembolism (VTE). With an exclusive biliary route of elimination, betrixabanwill be beneficial for patients with renal impairment. Roche and TeaRx are exploring a group of oral FXa inhibitors for the prevention of deep vein thrombosis (DVT), pulmonary embolism and stroke prevention in atrial fibrillation (SPAF). TeaRxaban,the leading agent, is in PhaseII evaluation for the prevention of thrombosis following orthopaedic surgeries.

Tecarfarin (ATI 5923; Armetheon), a selective inhibitor of VKOR, has completed a pivotal PhaseIII trial for a patient population that includes individuals with prosthetic heart valves. Tecarfarin has a readily available antidote in vitaminK, and Armetheon anticipates one further pivotal clinical trial with filings in the European Union and United States expected in early 2017.

Regado Biosciences is studying REG1 (PhaseIII; a two-component system consisting of pegnivacogin, an aptamer specifically targeting coagulation factorIXa, and its complementary oligonucleotide active control agent, anivamersen) for use during revascularization procedures such as PCI. REG1 has been granted fast track designation by the FDA.

Thrombolytic agents in development include desmoteplase (Lundbeck), a novel plasminogen activator in PhaseIII trialsfor acute ischaemic stroke. It was granted fast-track status by the FDA in March. THR18 (D-Pharm), a thrombolytic peptide derived from plasminogen activator inhibitor1 (PAI1), is in PhaseIIa trials for the treatment of stroke. It is designed to be co-administered with tissue-type plasminogen activator (tPA) to extend the duration of the therapeutic window of the latter and minimize its adverse effects.

Several marketed antithrombotics are also undergoing large and extensive clinical development programmes to expand into wider indications (http://www.nature.com/nrd/journal/v13/n8/full/nrd4365.html#supplementary-information

Web End =Supplementary http://www.nature.com/nrd/journal/v13/n8/full/nrd4365.html#supplementary-information

Web End =information S1 (table)).

A major challenge facing the antithrombotic field is a paucity of antidotes to manage bleeding complications. Portolais developing andexanet alfa against FXa inhibitors. PhaseII data showed rapid reversal of the anticoagulant activity of apixaban (Eliquis; Pfizer/Bristol-Myers Squibb) and the antidote is also being evaluated with rivaroxaban (Xarelto; Bayer/Janssen) and

edoxaban (Lixiana; Daiichi Sankyo).

A pivotal PhaseIII study in healthy volunteers is currently underway.

Other antidotes in early-stage development include the OAC-targeting aripazine (Perosphere) and idarucizumab (Boehringer Ingelheim), a highly specific and humanized antibody fragment that can neutralize the univalent DTI dabigatran etexilate (Pradaxa; Boehringer Ingelheim).

Market indicators

Antithrombotic agents generated sales of US$23.5billion worldwide in 2013, representing 53.1% of sales for haematology agents and 2.7% of the global pharmaceutical market (source: IMS Health Ltd., IMS Midas; 2014). Although it is highly competitive and fairly saturated, the global antithrombotics market still offers good prospects of growth and is expected to reach $25.9billion by 2018 (compound annual growth rate: 2.0%).

PAIs were by far the largest category with sales of $9.5billion (FIG.1). Clopidogrel (Plavix; Sanofi/Bristol-Myers Squibb) led the market with global sales of $2.3billion in 2013 (23.6% class share). The drug, however, cannot be metabolized by patients with a mutation in the CYP2C19 gene and is associated with an FDA black box warning. Following patent expiry in May 2012, sales of clopidogrel have been in sharp decline. More efficacious drugs in this class include prasugrel (Effient; Lilly) and ticagrelor (Brilinta; AstraZeneca).

LMWHs had sales of $6.5billion in 2013 and formed the second-largest class. Enoxaparin (Lovenox; Sanofi), the leading drug, claimed 40.5% class share. The third leading class, DTIs, had sales of $2.4billion, with dabigatran etexilate dominating sales (73.6% class share).

Direct FXa inhibitors generated $2.1billion in 2013. Rivaroxaban, indicated for atrial fibrillation, is the leading drugin this class, accounting for 93.6% of sales. Apixaban and edoxaban are late entrants and claim only a small share.

Fibrinolytics were worth $1.3billion, with alteplase (Activase; Roche/Boehringer Ingelheim), a tPA, leading sales in this class (53.0% class share). The VKA class with sales of $640 million is led by warfarin (Coumadin; Bristol-Myers Squibb) with a 23.0% class share.

The antithrombotic market is hindered by the lack of comparative efficacy data to quantify the equivalence or superiority of drugs to existing therapies. The benefits of newer treatments are therefore difficult to evaluate without head-to-head clinical trials.

The market also suffers from generic erosion, especially after the patent expiry of Plavix and Lovenox. By 2018, Effient, Brilinta and Pradaxa will lose patent protection. However, the availability of antidotes and the successful uptake of newer drugs will drive future growth, with OACs offering the potential to replace the large warfarin market.

Kritika Chaudhari is a freelance research analyst in Nottingham, UK.

Bashar Hamad, Ph.D., and Basharut A. Syed, Ph.D., are at IMS Health Ltd, 210 Pentonville Road,

London N1 9JY, UK. e-mails: mailto:[email protected]

Web End [email protected] ;

mailto:[email protected]

Web End [email protected] ; mailto:[email protected]

Web End [email protected]

doi:10.1038/nrd4365 Published online 4 July 2014

Competing interests statements

The authors declare no competing financial interests.

FURTHER INFORMATION

WHO factsheet N317: http://www.who.int/mediacentre/factsheets/fs317/en/

Web End =http://www.who.int/mediacentre/factsheets/fs317/en/

SUPPLEMENTARY INFORMATION

See online article: http://www.nature.com/nrd/journal/v13/n8/full/nrd4365.html#supplementary-information

Web End =S1 (table)

ALL LINKS ARE ACTIVE IN THE ONLINE PDF

2013 2018

2.7%27.8%

40.4%

3.6%

10.4%

9.6%

3.7% 2.0%

18.3%

19.3%

5.8%

5.3%

US$23.5 billion

US$25.9 billion

Vitamin K antagonists LMWHPlatelet aggregation inhibitors FibrinolyticsDirect thrombin inhibitorsDirect factor Xa inhibitorsOther antithrombotic agents

32.6%

18.4%

Figure 1 | Antithrombotic drug class sales in 2013 and 2018 (estimated). LMWH, low-molecular-weight heparin. Source: IMS Health Ltd., IMS Midas; 2014.

Nature Reviews | Drug Discovery

572 | AUGUST 2014 | VOLUME 13 www.nature.com/reviews/drugdisc

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