This week's tentative approval for Omnitrope (human growth hormone) in Europe bodes well for Novartis' Sandoz unit, which has been fighting tooth and nail to get biogenerics on the market.  A copy of Pfizer's Genotropin, which is worth more than $800 million per year to Pfizer, Omnitrope is a great start for Sandoz's would-be biogeneric business.  The European Medicines Agency (EMA)'s Committee on Medicinal Products for Human Use (CHMP) has given the drug a nod, which could also put pressure on the U.S. FDA to approve it. (Novartis press release)

Another beneficiary, however, could be Sandoz's little US partner, Momenta Pharmaceuticals.  At the end of last summer, Momenta and Sandoz created a stir when the companies submitted an abbreviated new drug application (ANDA) for M-enoxaparin to the FDA. Their application is a particularly bold move because everyone, including the FDA, seems to be uncertain about what the rules are for biogenerics.

The two companies report that Momenta has used advanced technology to create a copy of Sanofi-Aventis's popular low-molecular-weight heparin (LMWH), Lovenox.  To date, that drug has never been fully characterized, and Sanofi has been hoping to keep it that way, making it impossible for other companies to claim they have a real copy.  Momenta and Sandoz are not the only ones hoping to take a bite out of Sanofi's profits: Both Teva Pharmaceutical Industries and Amphastar Pharmaceuticals filed applications in 2003 for generic forms of Lovenox, but they are using more traditional approaches to produce those drugs.  Momenta's novel technology paired with Sandoz's longtime generics business experience is an intriguing mix, however, especially because Sandoz has already sued the FDA for issuing a non-decision on Sandoz's earlier application for Omnitrope.  

A $3 Billion Market

In its various forms, heparin is the most commonly employed antithrombotic, or clot buster, representing a market of approximately $3 billion per year.  Heparin or related drugs are used today to treat and prevent deep vein thrombosis (DVT), pulmonary embolism (PE), and peripheral arterial embolism in acute coronary syndromes (ACS).

A highly complex molecule comprising branched carbohydrates, heparin is derived from animal tissue and has a range of biological activity.  Because of the molecule's unpredictable behavior, patients have to be carefully monitored when taking heparin.  One of the biggest recent advances in antithrombotic therapy was the realization that fractionated heparin had some important advantages over the larger pre-fractionated molecule. The fragmented form of the molecule does not bind as easily to proteins, blood cells, and other molecules. Hence, it is more bioavailable, has a longer half-life, and is generally more predictable in the body, making it easier to determine a therapeutic dose.  However, the LMWHs seem to work just as well, and to be just as safe, as the unfragmented form. (See Gould, M.K., et al. Annals of Int. Med.) Sanofi-Aventis's Lovenox was first launched in the United States in 1993 and is the most widely prescribed LMWH, with reported sales of $2.14 billion in 2005.  The process Sanofi-Aventis uses for production of Lovenox is, naturally, standardized to ensure consistent quality and activity. 

Heparin with a Twist

Momenta has developed both a generic version of Lovenox and a new "rationally engineered" antithrombotic called M118.  While the first drug aims to be a cheaper version of the popular LMWH, the second drug has features that Momenta hopes will make it ideal for patients who are being treated in the emergency room for ACS.  LMWHs, for example, are only partially reversible, which is a problem in ACS patients who may need surgery or angioplasty. 

Creating either of these two types of drugs would be difficult for most companies to achieve, but Momenta says its key advantage is the core technology on which the company is based.

Momenta uses dozens of proprietary enzymes, each specific for a given type of carbohydrate or particular position of carbohydrate branch structure.  By using these enzymes as reagents and measuring the resulting composition of the fragments produced by a specific enzyme, Momenta is able to more rapidly and accurately determine the composition and precise structure of carbohydrate-based glycosylation.  To develop a generic version of Lovenox, the company has had to determine the composition and structure of the approved product, and then demonstrate that the generic version contains the same active ingredients.  In addition, Momenta had to develop a production process that would result in fractionated heparin that was the same in composition as Lovenox, and for this purpose, the ability to conduct analysis and composition studies was also critical. 

But Momenta does not believe that providing a generic alternative to Lovenox represents the only attractive opportunity in this segment.  The ability to analyze the structure and sequence of even smaller fragments of heparin provides a means to conduct structure-activity analysis.  For the first time, the multiple biological activities of heparin can be disaggregated into the specific structures associated with a given activity.  This capability allowed Momenta to begin asking cardiologists what the ideal blend of activities of heparin might be, including activity that might better be reduced or eliminated. 

The analytical capability to correlate structure with biological activity would be of limited value if it were then extremely difficult to obtain the specific fragments containing the correct structures, but here the core capabilities of Momenta again come into play.  Many of the same enzymes used as analytical reagents to cleave carbohydrate structures can also be used to selectively cleave and synthesize certain specific branching attachments.  In this way, it becomes possible to engineer a product with properties that are different from those of any standard LMWH. 

One other advantage Momenta is trying to develop is a new delivery method for biologics.  Because proteins are so large, they usually must be injected. In some cases, injection is not just inconvenient but causes serious problems because it may take too long for the drug to be fully distributed.  Momenta reports that it has determined that sugars can help transport large molecules such as proteins across membranes deep in the lungs.  Delivery via inhalation, particularly if enhanced by selective glycosylation, could result in very rapid delivery of the drug.  The company is hoping to exploit just such a system to allow administration of  proteins via pulmonary delivery. In particular, the company is looking at interferon-beta, erythropoietin, insulin, and human growth hormone, as well as LMWH.

Biogeneric Heparin on the Horizon?

Sanofi-Aventis is now being pressed on all sides by these generic versions of Lovenox.  Novopharm, a wholly owned subsidiary of Teva, has already received approval in Canada for a generic enoxaparin, and Sanofi-Aventis has been fighting a losing legal battle to defend the drug's patent a little longer.  So, while it is not clear whether Momenta will win this particular race, a LMWH will probably be one of the first biogenerics approved.  A win for Momenta would be a win not just for the company's unique technology but for the biogenerics industry as a whole.

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