Rescuing Patent-Less Proteins from the Drug Development Dustbin

11/6/12

Observe due measure, for right timing is in all things the most important factor.”

The Greek poet Hesiod wasn’t referring to the drug development process when he wrote these words, but they certainly apply to that setting. Back in the early days of the biotechnology industry, a number of newly identified proteins were considered for clinical trials. A few of them became marketed drugs [e.g. IL-2 (Proleukin), GM-CSF (Leukine), and erythropoietin (Epogen)], but a lot of these molecules were either never tested in humans, or failed in the clinic. Why?

1) The biology was not understood well enough in terms of a role in a specific disease.

2) Manufacturing sufficient quantities of biologically active protein in a cost-effective manner was difficult.

3) Companies that discovered them had insufficient capital and/or manpower to put them into clinical trials.

4) Toxicity was observed in preclinical testing.

5) Some proteins identified by academic investigators lacked patent protection.

6) The dosing regimen may have been wrong.

7) The design of the clinical trial was improper, was run poorly, or couldn’t recruit enough patients.

Any one of these problems might have prevented a positive outcome from being achieved. A great deal more research has been done on these proteins in the 20 or so years since they were discovered. We now have a much better (though still imperfect) understanding of how they function then we did in 1980-1995, when the majority of genes encoding these proteins were cloned and patented. During this time we’ve learned how many of these proteins are regulated, their mechanisms of action, and their physiological roles in both normal and disease states. The question is: given this new information, what can we do to resurrect some of these discarded proteins and get them back into the clinic?

We’re not talking about just a couple of molecules. A short list of proteins with remarkable biological activities might include a large number of the 37 known interleukins as well as a number of cytokines, growth factors, chemokines, and numerous activators and inhibitors of various receptors. A significant percentage of their “composition of matter” as well as their “method of use” patents have either expired, or are about to. As a result, the majority of these molecules would be fair game for other companies to work on and develop as drugs. However, this is unlikely to happen because most biopharma companies will not commit themselves to the time, expense, and risk of trying to advance them without patent protection. The lack of patent protection casts a long shadow over their future development.

Some of these proteins never got to the starting line in the drug development race, while others tripped and fell going over one of the first few hurdles. Manufacturing problems (e.g. low yields, poor biological activity, and limited production capacity in the industry) may have hindered the development. Generating sufficient quantities of low-yield proteins for clinical trials was so expensive back then that some of them were doomed from the start. Advances in producing recombinant proteins have significantly increased yields and therefore lowered their costs.

Most recombinant proteins were manufactured in either yeast or bacteria back in the early days of the industry. While this provided a good platform for some drugs, it became apparent that some proteins made via these processes were active in cell culture, but lacked biological activity in the body. A protein that I discovered was manufactured in both yeast and mammalian cells, and then their biological half-lives were measured in a head-to-head experiment in mice. The two forms of the protein were equally active in cell culture, but only the mammalian derived protein showed strong biological activity in animals. Similar findings were seen with other proteins, and a gradual shift took place: more and more drugs are now made in mammalian cell culture. Many recombinant proteins may have failed to move to or through clinical trials because they were manufactured in either yeast or bacteria instead of mammalian cells.

So how do we enable these potential medicines to get a second chance in the clinic? Potential … Next Page »

Stewart Lyman is Owner and Manager of Lyman BioPharma Consulting LLC in Seattle. He provides strategic advice to clients on their research programs, collaboration management issues, as well as preclinical data reviews. Follow @

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  • Sirid Kellermann

    Stewart, perhaps instead of an auction format, a lottery could work – provided lottery entrants were vetted on some minimal criteria (by whom?) and they had to show progress on the R&D after 2 years or cede their rights. Devil’s in the details as usual. I do think there’s a role to be played by both public sector (NCATS?) and private; the consortium currently under development may provide a model, if not a forum, to find ways to make the most of this truly low-hanging fruit. It would be a shame if we lacked the creativity and collaborative spirit to overcome the hurdles you’ve described.

  • Bobby Diggs

    Are data exclusivity provisions in the U.S. limited to 3 years for small molecules that are not novel (e.g., don’t qualify for NCE status)? If so, perhaps better to site 3 years when talking about drug repositioning. As for biologics, it seems 12 years of exclusivity may be incentive enough to start a program. And maybe methods directed to commercially manufacturing and delivering therapeutically effective doses might be patentable and offer some additional protection. In any case, an interesting topic – and you’ve presented it well. It will be interesting to see how Sanofi handles Lemtrada for MS. Good case study.

  • SK

    There is already a bill proposed to deal with the issue of ‘dormant therapies’ with insufficient patent protection – the MODDERN Cures Act – it would grant 15 years of data exclusivity. Although perhaps pharmaceutical companies would still not risk developing a drug without a patent if there is no means to prevent other companies from conducting clinical trials (i.e. a “race” to regulatory approval would be too risky). In that case, exclusivity could be secured to the first company which establishes ‘priority’ by publishing a clinical trial using the ‘dormant therapy’ as a protocol, with a new clinical trial required within 2 years using the same protocol or priority is lost. An auction or lottery system could also work.