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Half-a-million people die every year in Europe due to deep vein thrombosis (DVT) and pulmonary embolism (PE). Therefore, the increase in the treatment-seeking population will lead to further market growth in the field of anti-coagulation. Heparins are anticoagulants primarily used to prevent and treat venous thrombosis, PE and acute coronary syndrome. They are also used in haemodialysis and extracorporeal circulation and other conditions with increased risk of blood clotting. The prevalence of DVT and PE has increased remarkably in both Europe and North America. Because heparin is one of the foremost clinical anticoagulants, the rising incidence of coagulation disorders will in turn fuel demand for heparin products. The global heparin market stood at US$8.2 billion in 2014, exhibiting a compound annual growth rate of 6.3% between 2015 and 2023. The market is expected to reach US$14.3 billion by the end of 2023.1
Heparin usage will increase even more in the next ten years due to a number of other non-anticoagulant properties. These include anti-tumour, anti-inflammatory and anti-proliferative actions (in pathologies such as nephrotic syndrome and Alzheimer’s disease). They are therefore currently being investigated as concomitant therapy in malignant, rheumatologic, rare infectious, specific cardiologic and pregnancy related diseases (Table 1).2 Low-molecular weight heparins (LMWHs) are more frequently prescribed and investigated in the new indications due to the lower number of side effects (heparin-induced thrombocytopaenia (HIT), osteoporosis, hair loss, decrease in antithrombin (AT)), the lack of need for laboratory guided dose adjustment (activated partial thromboplastin time (aPTT)) has to be adjusted to a two- to three-fold prolongation with unfractionated heparin (UFH)) and the added benefit of subcutaneous injections administered only once- or twice-daily compared with UFH.3
All heparins require AT to speed up their anticoagulant activity about 1000-fold by inhibiting mainly factors Xa and thrombin. The interaction is driven strongly by the molecular weight and the sulphate groups of the saccharides comprising the heparin chain. UFH inhibits via AT factor Xa and thrombin in a ratio of about 1:1. LMWHs inhibit mainly factor Xa and to a lesser extent also thrombin with a ratio of about 4:1. This ratio is affected by the mean molecular weight of LMWHs and their sulphation pattern, increasing the ratio from about two to six with lowering the molecular weight and unaltered sulphation pattern. Desulphation may occur during the chemical degradation of UFH to a LMWH preparation.4
Non-anticoagulant properties of heparins
The non-anticoagulant properties of heparins, specifically of LMWHs, are independent of their AT binding sequence. The sulphation pattern and the molecular weight are more important. Heparin exhibits this activity by neutralising cationic mediators, inhibiting adhesion molecules, and inhibiting heparinase, all of which are involved in leukocyte recruitment into tissues. Similarly, cell adhesion-inhibiting properties of heparin have been found, which confer anti-metastatic activities. Heparin also targets P- and L-selectin and integrin activity, preventing cancer progression. Studies are being conducted to investigate the use of heparin as an anti-inflammatory and anti-tumour agent. Nevertheless it is the commercial LMWHs that are adopted and studied for their clinical benefit in new indications.2
Patent expiry
The patents of LMWHs have now expired. Subsequently, the market potential of LMWHs has continuously grown owing to increased use in a greater number of countries and potential new indications. Enoxaparin is the best selling LMWH worldwide. Therefore pharmaceutical companies in many countries produce copies of LMWH. They are produced either as biosimilars or named generic versions of the branded LMWH. Specifically, copies of enoxaparin are available in North and South America and Asian countries. In Australia and Europe the regulatory bodies developed specific requirements for approval of biosimilar LMWHs.5,6 Africa is presently not included so far in this development.2
Potential advantages of biosimilar LMWHs
The primary drive for development of biosimilar LMWHs is the profit potential for some pharmaceutical industries in this market. Secondary drives include the reduction of daily costs of the treatment as a benefit for health care systems. Another benefit lies in the production of biosimilar compounds in developing countries, which provides employment and therefore stimulate economic growth. However, the latter arguments can be regarded as less relevant than the primary drive. Several pharmaceutical companies produce copies of enoxaparin in Argentina, Brazil, Chile, Columbia, Egypt, Ecuador, Georgia, India, Morocco, Myanmar, Peru, The Philippines, South Korea, Tunisia, Turkey, USA, and Venezuela. It is no surprise that they also produce a biosimilar enoxaparin. This reflects the increasing need and consequently the high competition in the LMWHs market.
Controversies of biosimilar LMWHs
The definition of copied products of LMWHs differs between continents. In Europe and Australia, LMWHs are considered biological products derived from animal tissues and are therefore named ‘biosimilar LMWHs’, whereas in the US they are regarded as non-biological chemicals due to their non-protein structure and are called ‘generic LMWHs’. The consequence of these differences is mainly, that biosimilar drugs require defined clinical studies in patients that compare against the branded drug, whereas generic compounds undergo a shortened approval process with only in vitro comparison and few pharmacokinetic/pharmacodynamics investigations in healthy subjects. Accordingly, the requirement for approval of copies of LMWHs differs between the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA).5
Another difference arises between the EMA and recommendations of scientific communities. The EMA states that a clinical study is needed in a patient group with high risk of developing VTE, such as elective primary hip or knee replacement surgery, in order to demonstrate efficacy and safety in a limited number of patients using a low dose of the biosimilar LMWH compared with the branded LMWH. The request for approval can be extended to other indications using high doses of the biosimilar LMWH. The scientific bodies agree with the clinical study proposed by the EMA but require a non-inferiority design. They also stress the need for studies in high-risk groups for development of thromboembolism (such as unstable angina) to use a high dose of the biosimilar LMWH compared with the branded LMWH and a non-inferiority study design. The generation of heparin-platelet factor 4 (H-PF4)5 antibodies leads to the development of HIT type II. Therefore the scientific bodies ask for data on the generation of these antibodies in patients in the clinical studies to demonstrate the safety of a biosimilar LMWH.3
International statements
The statements of the European Medicines Agency (EMA), the Scientific and Standardization Committee, the International Society on Thrombosis and Haemostasis, the International Union of Angiology, the North American Thrombosis Forum and the South Asian Society on Atherosclerosis and Thrombosis7 differed substantially from those of the FDA for the approval of a generic version of a LMWH. The EMA published a concept paper aiming to develop new guidelines. Several publications commenting on the differences between the actual FDA and EMA guidelines are available.5 The consensus of the working party for the production of generic LMWHs of the Scientific and Standardisation Committee Subcommittee on Control of Anticoagulation of the International Society on Thrombosis and Haemostasis is currently generating a revised statement to harmonise the differences between the currently available guidelines.8
Recommendations for the production of biosimilar LMWHs
To ensure safety and efficacy, the following rcomemendations have been made:8
- The origin of the starting material (animal tissue and country of origin) of the originator and the generic LMWH should be described exactly as in the monograph of the originator product.
- The physicochemical characterisation of a biosimilar LMWH has to be compared with the branded version of the LMWH using antithrombin-affinity chromatography, heparinise-I digestion matrix-assisted laser desorption/nuclear magnetic resonance (MALDI-NMR)
- techniques.
- Analysis of lot-to-lot variations should be performed. NMR should detect impurities. Other techniques should not be allowed.
- In vitro studies should not demonstrate different in vitro effects on various coagulation parameters as well as no differences in pharmacodynamic effects in healthy human volunteers.
- Thrombin generation inhibition, release of tissue factor pathway inhibitor, factor Xa and thrombin inhibition should be included.
- Animal pharmacology studies should include acute, chronic, and repeated toxicity studies in accordance with the good laboratory practice guidelines in two animal species using different dosages comparing the biosimilar and the originator product.
- The effects should be compared in animal thrombosis models of the venous and the arterial system and in a bleeding model.
- Phase I clinical trials in human volunteers should be performed using a low prophylactic and a high therapeutic dose over five to seven days each.
- If differences between the branded and biosimilar version of a LMWH are detected by these investigations and if the manufacturer of the generic LMWH decides to further develop the product, then a clinical study in postoperative VTE (total knee or hip replacement surgery) and in a cardiology indication (preferentially treatment of unstable angina) will be required. This recommendation from the EMA is different from that of the FDA.
- After approval of a generic LMWH,
- a robust post-marketing surveillance system of the manufacturer in close co-operation with the FDA or EMA should be mandatory to identify expected and unexpected side effects as early as possible to ensure patient safety.
Limitations of biosimilar LMWHs
The limitations for the use of biosimilar LMWHs include:
- Chemical methods are used to cleave the polysaccharide chains of heparin (range of molecular weight of the polysaccharide chains in one LMWH preparation 2000 to 10,000 Dalton (Figure 1)) to different disaccharides. The sequence of the resulting disaccharide units is not included in this definition of similarity. A reconstruction of the polysaccharide chains of heparin from the disaccharides would be necessary to fully demonstrate the similarity between the branded and biosimilar LMWH.
- Pharmacological studies in volunteers include only determination of the inhibition of factor Xa and thrombin. The effects on activated partial thromboplastin time (aPTT), and prothrombin time (PT), release of tissue factor pathway inhibitor, and generation of H-PF4 antibodies should be included as outlined by recommendations of scientific bodies.
- At present only one study of 200 patients has been published demonstrating a non-different antithrombotic effect of a generic enoxaparin versus the original, branded enoxaparin in patients undergoing elective hip replacement surgery.9 This study is far too small to draw any
- useful conclusion.
Perspectives of biosimilar LMWHs in Europe
Clinical studies to demonstrate the efficacy and safety of a biosimilar LMWH in two individual settings using a low and a high dose of the copied LMWH should be required. However, such studies will be very costly and therefore difficult to perform.
It is essential to note the import of copies of LMWHs through other countries. Lowering the daily treatment costs may be the main driver for introducing such a biosimilar LMWH into the European market.
Currently, the relative shortage in the production of LMWHs has led to the discussion in American countries to re-introduce UFH from bovine lung, ovine and other sources to produce LMWH. It has to be remembered that the heparin crisis in 20077 originated from an over-sulphation of a LMWH preparation. During this crisis about 200 patients died, most frequently while on chronic haemodialysis. Following the requirements of the EMA and of the scientific bodies, adequate chemical and pharmacological characterisation and clinical studies should demonstrate the non-inferior efficacy and safety of such new LMWH compound compared with a standard LMWH10,11 to avoid another crisis.
Conclusions
As long as not all criteria of sameness, clinical efficacy and safety of a biosimilar LMWH to an originator are being demonstrated, the branded LMWHs continue to be preferable over the biosimilar LMWHs to ensure the safety of treatment of patients.
Lowering the daily treatment costs by 10–20% should not be the main driver to introduce biosimilar LMWHs at the risk of known or unforeseeable side effects. This is a lesson that should be learned from the so-called heparin-crisis.8
References
1 www.transparencymarketresearch.com/heparin−market.html (accessed September 2016)
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3 Harenberg J et al. On behalf of the Subcommittee on Control of Anticoagulation of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis. Recommendations on biosimilar low-molecular-weight heparins. J Thromb Haemost 2009;7:1222−5.
4 Rudd TR, Guimond SE, Skidmore MA. Influence of substitution pattern and cation binding on conformation and activity in heparin derivatives. Glycobiology 2007;17:983−93.
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7 Kalodiki E, Leong W, SASAT and Task Force on Generic LMWHs. SASAT (South Asian Society on Atherosclerosis and Thrombosis) proposal for regulatory guidelines for generic low molecular weight heparins (LMWHs). Clin Appl Thromb Hemost 2009;15:8−11.
8 Harenberg J et al. Subcommittee on Control of Anticoagulation, Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis. Update of the recommendations on biosimilar low-molecular-weight heparins from the Scientific Subcommittee on Control of Anticoagulation of the International Society on Thrombosis and Haemostasis. J Thromb Haemost 2013;11:1421−5.
9 Gomes M et al. An open label, non−randomized, prospective clinical trial evaluating the immunogenicity of branded enoxaparin versus biosimilars in healthy volunteers. Clin Appl Thromb Hemost 2011;17:66−9.
10 Kalodiki E, Fareed J. New and generic anticoagulants and biosimilars: safety considerations. Clin Appl Thromb Hemost 2011;17:136−9.
11 Ofosu FA. A review of the two major regulatory pathways for non-proprietary low-molecular-weight heparins. Thromb Haemost 2012;107:201−14.
