US-based biotechnology company Momenta Pharmaceuticals has received US Food and Drug Adminitsration (FDA) marketing approval for its generic version of Sanofi-Aventis's antithrombotic drug Lovenox (enoxaparin). As a result of the agency's announcement, Momenta's share price rose from US$11.9 to US$21.7, an 82% increase. Lovenox is Sanofi-Aventis's second best-selling drug, generating revenue of US$3.9bn in 2009, of which the US market accounted for almost two thirds.
Momenta's Abbreviated New Drug Application (ANDA) for enoxaparin was filed with the FDA in 2005 and since then, other generic drugmakers have also challenged Sanofi-Aventis patent on Lovenox. Despite a previous US Supreme Court ruling that Sanofi-Aventis's patent was not enforceable, the French drugmaker had asked for a temporary restraining order and a preliminary injunction that would require the FDA to withdraw its approval for the generic drug.
The recent approval of a generic version of enoxaparin could therefore have much broader implications for the biotechnology and generic drug industries. The FDA's decision has raised concerns among drugmakers as some believe it will set a precedent for the launch of generic versions of biological drugs without the need for extensive clinical trials. Sanofi-Aventis believes that generic enoxaparin should not be approved because the generic drug has not been subjected to extensive clinical trials to demonstrate its efficacy, which is the standard FDA requirement for all biological drugs.
Enoxaparin has not been classified as a biological drug for ANDA application; instead it was treated as a low molecular weight heparin (LMWH). Therefore, the only requirement for FDA approval is that Momenta produces extensive evidence that the generic version has identical composition to the originator drug.
However, the treatment of enoxaparin as a non-biological drug has been questioned, as the antithrombotic medicine is composed of a mixture of linear polysaccharide molecules of variable chain lengths and molecular weights, produced by either chemical or enzymatic depolymerisation of standard unfractionated heparin derived from porcine intestinal mucosa.
A Very Complex Drug Composition
It is BMI's view that manufacturing enoxaparin to the exact composition of the originator's drug poses a significant challenge due to the complexity of the drug's composition. Enoxaparin's structure is characterised by a 2-O-disulfo-4-enepyranosuronic acid group at one end of the sugar chain and a 2-N, 6-O-disulfo-D-glucosamine at the other. About 20% of the enoxaparin structure contains an 1,6 anhydro derivative on the reducing end of the polysaccharide chain.
As the number of saccharide units increases (the n value), the longer the sugar chain and the greater its molecular weight. Approximately 20% of the sugar chains in the drug have a molecular weight of less than 2000 Daltons, 68% of the sugar molecules weigh between 2,000 and 8,000 Daltons and about 18% are above 8,000 Daltons.
It is fundamental that the generic drugmaker is able to ensure that enoxaparin has this exact composition, as the drug's anticoagulant and antithrombotic action depends on the sugar chain's binding affinity to thrombin (anti-FIIa activity), which in turn is defined by the distribution of chain lengths in the mixture and the specific chemical features within each sugar chain constituting the drug.
The safety and efficacy of the enoxaparin is defined by its ADME (absorption, distribution, metabolism and excretion) characteristics, which are also determined by the distribution of polysaccharide chain lengths within enoxaparin's composition. For instance, if the amount of short sugar chains in the mixture is higher than it should be, then the drug's affinity for plasma and matrix proteins would decrease, resulting in an increase in the bioavailability of the drug in the body, lowering the margin for the highest safe dose.
Will Other Generic Drugmakers Follow Momenta's Footsteps?
The reason Momenta Pharmaceuticals succeeded in obtaining FDA approval for the generic antithrombotic is that it was able to provide evidence that the generic drug version had exactly the same composition as Sanofi's Lovenox.
In order to achieve that outcome, Momenta partnered with Sandoz, the generic division of Novartis. The partnership has invested in the development of a proprietary technology platform consisting of patented enzymes to break down the porcine standard unfractionated heparin, the development of specialist software to combine analytical data from mass spectroscopy and nuclear magnetic resonance and capillary electrophoresis - among other analytical techniques - to analyse the components of the originator's drug as well as the structure and arrangements of sugar chains in Lovenox.
The development of a generic version of such a complex drug is a very resource-intensive process and it is highly unlikely that ordinary generic drugmakers producing simple small molecules will be prepared to make the considerable investments required to significantly upgrade their technology base and produce enoxaparin. Momenta intends to apply its proprietary technology to the development of other complex generic drugs, such as Teva Pharmaceuticals' Copaxone (glatimer acetate), a random polymer found in myelin basic protein and used as an immunomodulator to treat multiple sclerosis.