Biotech Values

[DewDiligence]

Tuesday’s WSJ tells the MNTA story:

http://wsj.com

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One Start-Up's
Path to Making
Biotech Clones

By LEILA ABBOUD
Staff Reporter of THE WALL STREET JOURNAL
August 16, 2005

Can a tiny Massachusetts company help crack the code to marketing generic biotech drugs?

Since the advent of genetic engineering led to the earliest biotechnology drugs in the 1980s, the field has been among the most rarefied in the pharmaceutical industry. Both difficult and expensive to research and make, biotech drugs are derived from natural processes, not the chemicals used in conventional drugs. Their complexities have put them beyond the reach of generic drug companies wanting to market cheaper clones.

Not that some haven't tried: Generic drug makers such as Teva Pharmaceutical Industries Ltd. and Barr Pharmaceuticals Inc. have been working to decode the scientific processes specific to biotech drugs. So far, all have faced resistance from the biotech industry, as well as uncertainty at the Food and Drug Administration. As a result, not a single generic biotech drug, or biogeneric, exists on the market today.

The latest to try to fight its way into the thorny biogenerics field is Momenta Pharmaceuticals Inc. The company, founded by Massachusetts Institute of Technology scientists in 2001, is expected to apply to the FDA this month for the right to sell its generic version of Sanofi-Aventis' blockbuster drug Lovenox, a blood thinner. In doing so, Momenta is pushing the FDA to define its views on the central question in copying biotechnology drugs: just how much evidence do generic drug makers have to provide to prove their drugs are equivalent to the originals?

The stakes in the fight over biogenerics are high. For drug companies, they represent a huge, and growing, source of profits: Sales of biotechnology drugs in the U.S. rose 17% last year to reach $27.52 billion. Because of their high price tag, they also have a big financial impact on the employers and insurers who foot most of the bill for the nation's drug costs. A 10-month course of Genentech Inc.'s colon cancer drug Avastin, for example, costs about $49,000. Four months' worth of the colon cancer drug Erbitux, marketed by ImClone Systems Inc. and Bristol-Myers Squibb Co., costs about $38,400.

The FDA currently has no process for approving generic versions of most biotech drugs. That's because the 1984 law that allowed generics makers to shorten the FDA approval process applies only to traditional, chemically-based medicines. At the time of the law's passing, biotech drugs were uncommon. Congress will likely have to enact a new law to allow most biogenerics.

But companies such as Momenta are optimistically pushing ahead: Due to a bureaucratic quirk, the FDA has more legal freedom to approve copies of a handful of older and simpler biotech products. Since these drugs, which include Lovenox and human growth hormone, were approved as regular drugs, not biologics and not under a later, separate law on biotech drugs, the FDA could approve these products without a new law.

Behind Momenta's FDA application is a powerful new laboratory tool that the company says allowed it to map out Lovenox more clearly than ever before. At the heart of the scientists' effort is a new way of understanding the complex structure of sugars, which are key to many biological processes and some biotech drugs.

The MIT biochemists spent a decade developing a technique to identify and sequence sugars, something that has long eluded scientists. The ability to decode sugars and understand how they shape a drug's effects on the body are a key element in copying many biotech drugs.

The natural origins of biotech drugs make them bigger and far more complicated than conventional drugs; it's very hard to define a single chemical that is responsible for a biotech drug's effect. Lovenox, for example, is a complicated sugar molecule derived from pig's intestines. [I would have used the word “complex” instead of complicated—the point being that Lovenox is a mixture of several distinct molecules.]

The biotechnology industry maintains that the only way for generics to prove they are true, safe copies is to undergo lengthy and expensive clinical trials. Such a requirement wouldn't be feasible for generic drug makers because they couldn't afford to do multiyear, large trials and then sell drugs at deep discounts.

But an array of tools, including Momenta's sugar-sequencing technique, are increasing generic companies' ability to "characterize," or identify the structure and content of, biotech molecules. Techniques widely used in drug-industry labs, such as mass spectrometry and crystallography, have also greatly improved.

Armed with more knowledge, generic drug companies say they can reverse-engineer biotech drugs with more certainty, making extensive clinical tests unnecessary. "The better you can characterize a product, the more limited your clinical tests can potentially be," says Joerg Windisch who heads biopharmaceutical technical development at Novartis AG, which partnered with Momenta to develop and market a generic version of Lovenox, called M-enoxaparin.

But now these companies must persuade the FDA their new sugar-sequencing approach is valid. The battle over Lovenox could provide an indication of how regulators see the scientific issues over generic biotech drugs. Lovenox, which is used to prevent blood clots, is Sanofi-Aventis' top-selling drug, with $1.9 billion in sales in 2004.

Both Teva and Amphastar Pharmaceuticals Inc. applied in 2003 to the FDA to market generic versions of Lovenox. Those companies are still awaiting decisions. To prove equivalency, they used more conventional scientific techniques -- such as chromatography and measurements of molecular weight -- than the newer techniques employed by Momenta. They say they have provided enough data for approval.

Sanofi-Aventis disagrees. After the Teva and Amphastar FDA applications, Sanofi-Aventis petitioned the agency not to approve any generics of Lovenox unless the generic applicants did lengthy clinical trials to prove safety and efficacy, or used a manufacturing process equivalent to its own. The company went so far as to argue that its drug couldn't be copied safely, since about one-third of the molecule remain unknown, or uncharacterized, even by the company itself. Wyeth took a similar stance in 1997, when it waged a successful campaign to keep generics of its hormone therapy drug Premarin off the market.

As for Momenta, it says it has unlocked Lovenox's complex structure and engineered a process to manufacture it. The Cambridge, Mass., company says its application meets the FDA requirements for generics, showing that its version of Lovenox has the same active ingredient, administration route, dosage form, same duration of action and efficacy in the body. "With a complex drug like Lovenox, it was more of a challenge to demonstrate what the drug actually is than to replicate it," says Momenta Chief Executive Alan Crane.

Sanofi-Aventis spokeswoman Tricia Geoghegan says the company didn't have enough information to comment on Momenta's application, but stands by its petition to the FDA. "The company is not aware of any currently available technology that can accurately characterize all the components in Lovenox," Ms. Geoghegan says.

The FDA declined to comment on the pending generic applications or Momenta, and says it is working on a response to the Sanofi-Aventis petition.
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