The Protein Problem
Would-be biogenerics makers face two major obstacles in the U.S. market. The larger of the two is the lack of a regulatory framework governing generic protein drugs. But this problem is bound up with the other: how to prove that a generic biologic is chemically and therapeutically equivalent to the original. For conventional pharmaceuticals such as aspirin, or even state-of-the-art drugs like Lipitor or Viagra, the process is straightforward. These drugs comprise relatively simple, small molecules that generics makers can synthesize directly in the lab and then analyze chemically to ensure that they are pure and identical to the name-brand versions. The FDA approves generics based on this proof, plus small clinical trials that typically include about 30 patients, to show that the body metabolizes the copies in the same way that it does the originals. Since generics companies don’t have to conduct large and expensive clinical trials (or pay for the original R&D), they can sell the drugs cheaply and still turn a profit.
Protein drugs, in contrast, are huge, complicated molecules. Chemists can’t manufacture them cheaply, or in some cases at all, so biotech companies instead genetically engineer bacteria and other cells to do so. The reliance on living cells gives the process a black-box quality; small changes in, say, temperature or purification conditions can have unintended results, affecting how well a drug works or even causing severe side effects. Indeed, says Walter Moore, vice president of government affairs at Genentech, the firm that first produced recombinant insulin, “our products are defined not by their chemical makeup but by the process through which they are made.” To some extent, the FDA seems to agree; the agency approves not only the finished product for biotech drugs but also the production process, which is often subject to separate patents or held as a trade secret.
None of this, however, rules out copying protein drugs. Multiple patented versions of erythropoietin, insulin, human growth hormone, and interferon beta are sold in the United States. But each version varies slightly from the others and has gone through the full gamut of clinical testing required of a new drug – a qualification that some biotech innovators insist every protein drug, unique or copy, should have to meet. “This trade association would be uncomfortable with a process that didn’t include clinical trials,” says Sara Radcliffe, managing director for science and regulatory affairs for the Biotechnology Industry Organization. Such a requirement would effectively bar generic competition.
Emerging technologies, however, could improve the precision of protein characterization, helping to divorce biotech products from the processes used to make them – and perhaps reducing the amount of clinical testing necessary. Generics companies such as Israel’s Teva and GeneMedix in England, for instance, use ever improving analytical techniques and computational methods to accurately characterize the three-dimensional structures of proteins. Those structures – the products of exceedingly complicated series of twists and folds as the proteins are being manufactured in the cell – profoundly influence the molecules’ efficacy, potency, and side effects.
Startups such as Momenta Pharmaceuticals in the United States and U.K.-based Procognia have developed technologies to scrutinize another source of proteins’ fickleness: the sugar molecules that are often attached to them during their manufacture. The enzymes in mammalian and human cells that add these sugars to proteins follow rules that seem to vary with the cells’ growth conditions, so figuring out the number and types of sugars attached to a particular protein has proved especially challenging. Momenta has combined proprietary enzymes, traditional analytical techniques, and unique computational algorithms to precisely map such sugars. Procognia uses sugar-detecting arrays, analogous to gene chips that analyze gene sequences or activity, to do the same thing. “From a technical standpoint, I believe it’s possible to completely characterize a protein,” says Alan Crane, Momenta’s CEO. “If you can show it’s all the same, what are the arguments for not allowing a generic?”