FDA Decision a Blow For Genzyme—and Biogenerics?

4/22/08

I’m always hesitant to try to read the tea leaves on the future of biogenerics—those would-be lower-cost copies of protein-based biotech drugs. After all, the question of if, when, and how the FDA would create a mechanism for approving such drugs has been kicking around, unanswered, for almost as long as I’ve been covering biotech. But I’ve got to say the news yesterday that the FDA had rejected a request from Cambridge, MA’s Genzyme (NASDAQ: GENZ) for clearance to sell batches of one of its own already approved drugs, made at a different plant from the one that produced the drug for the original approval—well, that doesn’t look so good, for Genzyme or for biogenerics.

Genzyme has been trying to scale up production of the drug Myozyme, which was approved in 2006 for the treatment of an inherited muscle disorder called Pompe disease. The drug is already produced for the U.S. market at the company’s Framingham, MA, plant, but to meet demand Genzyme started churning it out on a much larger scale at a plant in Boston. Yesterday, the company said it had been informed by the FDA that the agency considered the Myozyme coming out of the Boston plant to be a new product, rather than more of the same stuff that’s already been approved, and that Genzyme would need to file a new application for the Boston-made Myozyme if it wants to sell it on the U.S. market. (Genzyme pointed out in its press release about the agency’s decision that marketing the Boston batches of the drug has already been approved in 40 other countries.)

One of the central arguments against allowing generics makers to produce copies of biotech drugs once the patents expire is that, since such drugs are made by living cells rather than precise chemistry, they’re very sensitive to tiny changes in the manufacturing process. Allowing another company to produce the drug, opponents of biogenerics warn, would be likely to result in a product that was not exactly the same as the original, and not necessarily as safe or effective as the original. Many observers have pointed to the Myozyme example as powerful support for this argument—here you have the same company making the same drug at different plants, and the products don’t come out identical. (I took a look at some of the arguments on both sides of this debate last summer, when Genzyme’s troubles with scaling up Myozyme production first came to light.)

As competing pieces of biogenerics legislation have inched their way through Congress, a critical question has been whether the FDA will ultimately require generics manufacturers to perform new clinical trials to get copycat protein drugs on the market. (One of the main reasons that makers of traditional generics can sell drugs more cheaply is that they are spared the huge expense of clinical trials.) If Myozyme is really a magic eight ball, signs point to ‘yes.’ To sell the Boston-made drug, Genzyme will have to submit more clinical-trial results. Luckily for the firm, the agency seems to be willing to accept data from a study that Genzyme had already undertaken to fulfill a post-marketing requirement.

All in all, Genzyme expects that the FDA’s latest action will push the U.S. commercial availability of Boston-made Myozyme back until the first quarter of next year. The company knocked $45 million off its 2008 sales projections for the drug and $0.10 off its 2008 per-share earnings projections. Shares of Genzyme opened today at $72.29, down 2.4 percent from yesterday’s close of $74.09.

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  • http://www.biopharma.com Ronald A. Rader

    This may not be as bad an omen for follow-on biologics/biosimilars in the the U.S. than is being portrayed by many. Nothing of substance has yet been disclosed, e.g., what are the structural and, perhaps, functional differences between enzyme manufactured at 160- and 2000-L scales. Obviously, there are at least some detectable structural differences for FDA to require a full BLA vs. supplemental filing.
    The problem is, presumably, that the products produced at two different scales, in two different facilities, etc. have been portrayed by Genzyme as being identical, interchangeable or truly (bio)generic. FDA has already stated that it essentially will not even consider such biologics approvals for years. Genzyme probably would have had a much easier time, and the new product already be approved, if it had developed the 2000-Liter-scale product much like a follow-on biologic or biosimilar would be, i.e., had conducted comparison trials and shown bioequivalence. If this were proven, even with some trivial structural differences (not affecting functionality), presumably the new product would simply have received a supplemental approval. I could be wrong, but I am not aware that Genzyme conducted such comparison trials. Another problem (from FDA’s perspective) is that Phase III-like trials meeting their primary endpoints for efficacy and safety with the new product have already been completed and reported (but not submitted). Between having full (vs. supplemental) approval-supporting trial data available (but not filed) and with some obvious detectable differences between the products, FDA presumably feels compelled to request Genzyme go for full approval as a new/different product.

    Ronald A. Rader
    Author:  Biopharmaceutical Products in the U.S. and European Markets
    E-mail:  biotech@biopharma.com
    Web site:  http://www.biopharma.com