“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 solutions will require creative thinking and eventual codification into law. Let’s focus our attention in two areas, patents and exclusivity agreements.
Patents, a cornerstone of technological advancement, give their holders the right to block others from practicing their inventions. Patent reform issues are a big concern in biopharma, where the industry is currently fighting to retain the ability to patent gene sequences, an effort opposed by many, including double helix co-discoverer James Watson. At least one industry critic insists that, “it is far from clear that we need any patents on medicines”. Patent concerns are not unique to those focused on drugs and diagnostics. Many people in the tech world are troubled by the use of patents as weapons of mass disruption. For example, both Google and Apple spent more money last year on buying patents and on patent lawsuits then they spent on R&D. There are also serious concerns about the rising costs associated with the legal actions of non-practicing entities, which are often derisively referred to as “patent trolls”. These costs detract from the ability of targeted companies to create new products.
There is a growing recognition that patent rules developed many years ago may simply be inadequate in a world of gene sequences and smart phones. The Australian Government recently announced plans to review its pharmaceutical patent system and will consider, among other things “new uses of known products”. A variety of intellectual property initiatives have been proposed in the tech world, from Twitter’s “Innovators Patent Agreement” to the idea of a “Defensive Patent License” to protect companies from the evil patent trolls who don’t invent things, but acquire patents and then sue or threaten to sue actual innovators for patent infringement. However, I am unaware of any proposed solutions in the biotech arena that would facilitate the commercialization of proteins covered by expired gene patents.
How would you go about resuscitating an expired patent? Should the original patent holder (or their assignee) be given preference in this process? Any solution should prevent deep-pocketed companies from buying up massive numbers of these patents, either to stack them on their own shelves, or simply to prevent others from using them. Perhaps auctioning off the patents would be a workable solution, though this would seriously disadvantage small biotechs at the expense of Big Pharma. The expired patents would have to be sold on an “as is” basis, without representation that they are valid, don’t infringe on other patents, and are immune to being challenged.
A second approach to protecting drugs from competition is to provide data exclusivity in drug applications. This approach currently grants protection of clinical test data that is developed by a company in the process of working up their drugs for eventual approval by the FDA. Competitors are specifically prohibited from submitting this information as part of their own FDA applications. They are required to run their own clinical trials and develop their own data set. Data exclusivity provisions in the U.S. are currently set at 5 years for small molecule drugs and 12 years for biologics (which are protein based medicines, like the ones being discussed here). Biopharma industry representatives are currently lobbying hard to make sure that 12-year data exclusivity provisions also become part of the Trans Pacific Partnership trade agreement that is being negotiated. Some public health care advocates worry that inclusion of such a clause will delay the introduction of biosimilars into the U.S. and thereby increase healthcare costs.
Data exclusivity provisions in the U.S. should apply to drugs created from molecules that have expired patents. The key question is: would drug makers attempt to revitalize a potential drug solely on the basis of the intellectual property protection provided by the data exclusivity provisions of the Affordable Care Act? Patents actually block competitors, whereas data exclusivity merely puts a roadblock in their path. Could other incentives be put in place to encourage biopharma firms to develop these older molecules into the medicines of tomorrow?
Resurrecting potentially useful (but never commercialized) proteins is distinct from another well-established process called drug repositioning, where biopharma companies look for new uses for older drugs. There are numerous examples of drugs that have been repurposed for new clinical indications. Perhaps the best known is Celgene’s thalidomide (Thalomid), which has been successfully used to treat both a complication of leprosy as well as multiple myeloma. This is the same drug that developed terrible notoriety in the 1960s for causing serious birth defects in the children of women who took it to combat morning sickness when they were pregnant.
A general solution that would encourage the development of molecules with expired patents would certainly help to foster medical advances and interventions. For example, the anti-inflammatory medicine oxyphenbutazone was patented and first marketed in the 1950s as a treatment for arthritis-like pain. More recently, however, this drug has been shown to sensitize drug resistant tuberculosis bacteria to other antimicrobial agents. Researchers have expressed doubts, however, that it will ever be tested in humans because drug companies couldn’t make any money on this off-patent drug. This argument, however, didn’t prevent doctors from demonstrating the effectiveness of using aspirin to treat a subset of individuals at high risk for developing colon cancer. It should come as no surprise that the NIH and foundations, not pharma companies, funded this latter trial.
It would most likely fall on the federal government to energize an alternative funding approach to test these older molecules in the clinic. This could be done in one of two ways. It could directly fund trials for some of these molecules. Given our nation’s massive debts and deficits, however, this approach doesn’t look too likely to be employed any time soon. The other possibility is to offer up incentives for effective treatments. Come up with a drug that is curative for drug resistant TB, for example, and earn a $3 billion reward for your efforts. No government payments would be required until and unless the treatment proves to be truly effective. I can envision investors funding companies that would compete for this (and similar) prizes; it would provide a third liquidation pathway for VCs besides acquisitions and IPOs. These large payments could turn out to be cost effective for the government. A cure for this and many other diseases could reduce, if not eliminate, the need to pay for costly treatments for Medicare and Medicaid patients. Non-profits might also be able to fund some of these clinical trials. They wouldn’t be bothered by the lack of financial return that will keep Big Pharma from focusing its attention on this area. However, the high cost of these trials will be a strong impediment for all but the best-funded organizations.
It’s a simple truth that patents on numerous proteins in the biopharma realm will expire before they reach clinical fruition. Smart scientists will eventually figure out which of these proteins may be useful as drugs, but their solutions may not be patentable. And without patent protection, many biopharma companies will simply avoid commercializing older molecules and technologies. Many complex issues will need to be resolved to facilitate this process, and making this happen won’t be easy. However, it’s time to start a dialog in the biopharmaceutical industry and work on coming up with creative solutions to this problem. We can then focus our attention on identifying and developing these biological diamonds in the rough.
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