Companies developing follow-on competitors to biologic drugs must do a lot of reverse-engineering and push the state of the art in molecular analytics
No drug is a monopoly forever. In February, the U.S. Food and Drug Administration (FDA) released draft guidelines on how follow-on rivals to biologic drugs (those made by living organisms) might take an abbreviated path to market without full clinical trials.
Even on an abbreviated path, firms developing “biosimilar” drugs are faced with far more preclinical and clinical work than needed for conventional generic drugs.
However, companies worldwide are rapidly gearing up for the challenge, targeting products including major anticancer antibodies that will soon lose patent protection. For example, generic drug maker Sandoz (Holzkirchen, Germany) is running clinical trials in Europe, Asia, and South America of a biosimilar version of Roche's (Basel, Switzerland) lymphoma and leukemia drug rituximab (Rituxan), which currently costs tens of thousands of dollars a year per patient. The rituximab patent expires in 2015.
Greater Complexities for Biosimilars
Conventional drugs are small molecules with defined chemical structures. Paclitaxel (Taxol), for instance, has just 113 atoms. Figuring out all the details of a synthetic pathway is by no means easy, but once chemists do, they can reliably make a generic chemical drug whose structure and behavior will be identical to the original.
“Chemical generics have never been shown to be different—they have the same efficacy and toxicity,” says Leslie Benet, PhD, professor of bioengineering and therapeutic sciences at the University of California, San Francisco.
Copying protein drugs, the main biologic candidates in oncology, is different. Mimicking these drugs is more difficult because they're made by cells, and often their complex structures are not fully understood. Companies trying to manufacture biosimilars must do a lot of the same work that the originator of the drug did.
With protein drugs, the process starts with inserting the gene for the protein drug into a rodent cell line, then repeatedly analyzing the products the cells make and cloning the cells that do it well.
From there, things become more complicated. The gene only codes for the chain of amino acids in the protein. Post-translational modifications are influenced by cell type, temperature, and many other factors that are, for the most part, not described in drug patents.
Creators of biosimilars must reverse-engineer the conditions that will nudge their cells to make protein drugs with all the right structural properties.
Some differences have a significant effect on a protein drug's efficacy and toxicity. Some don't. “The hard part is knowing what is clinically relevant,” says Janice Reichert, PhD, research assistant professor at the Tufts Center for the Study of Drug Development in Boston, MA.
One approach is to figure which higher-level properties are clinically relevant, and focus on replicating those.
Another, taken by Momenta Pharmaceuticals (Cambridge, MA) with Baxter (Deerfield, IL), is to try to mimic as exactly as possible every single detail of a protein drug.
Craig Wheeler, president and CEO of Momenta, which specializes in protein analytics, says good analysis of the original drug can reveal things about manufacturing, such as which strain of cells is used to make the drug. Wheeler says investing in analytics upfront will pay off in the long term by eliminating the need for extensive, expensive clinical trials.
“Analytics are improving all the time but there's still a lot we don't know,” says Richard Markus, head of development in the biosimilars division at Amgen (Thousand Oaks, CA), which will collaborate with Watson (Parsippany, NJ) on biosimilar cancer drugs. Clinical trials won't be needed to determine the correct dosage, but limited clinical studies of efficacy and safety will be required.
Investigating Drug Interchange
One concern is that pharmacists will switch a patient from a brand biologic drug to a biosimilar, with adverse effects. For this reason, the FDA is mandating higher standards for calling a biosimilar drug “interchangeable,” which would enable pharmacists to make such a substitution.
If a pharmacist switches a patient from the original drug to a biosimilar during the course of treatment, and that patient develops an immune reaction to the biosimilar, that drug may no longer be effective and this would likely have the same effect on the original drug as well. “In a case where there are very limited treatment options, then you have just eliminated one,” says Markus.
“At this time, it would be difficult as a scientific matter for a prospective biosimilar applicant to establish interchangeability” in its original application, the FDA guidelines note.
Overall, developers of biosimilars may have a hard scientific road ahead of them. “We need good data showing that these drugs really are similar,” says Reichert. She argues that drug companies should make their preclinical and clinical biosimilars data known by publishing it. “The underpinning of all of this is science,” she says.
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