By Kevin E. Noonan —

The comparative effectiveness of two Genentech drugs, Lucentis® and Avastin®, for the treatment of age-related macular degeneration (AMD) is currently the subject of a study by the National Eye Institutes (NEI) of the National Institutes of Health.  The reason:  the cost of Avastin® treatment (an off-label use, since Avastin® is approved only for treating colon and certain lung cancers), is much less than the cost of treating AMD with Lucentis® ($20-60/dose versus $2000/dose).  Perhaps not surprisingly, Genentech has refused to supply the NEI with either drug for the trial.  In an article in Tuesday’s Wall Street Journal, Dr. Arthur Levinson attempted to justify the decision.

In responding to questioning by reporter Marilyn Chase, Dr. Levinson (at left) recounted the history of the development of both drugs.  According to Dr. Levinson, Genentech’s inventor, Dr. Napoleone Ferrara, purified vascular endothelial growth factor (VEGF), a protein that induces blood vessels to form, and then showed that 90% of cancers overexpressed the protein.  This discovery was consistent with work, most famously by Dr. Judah Folkman, that cancer cells produce angiogenic factors that induce blood vessel proliferation in tumors as part of the natural progression of the disease.  Avastin®, a monoclonal antibody that interferes with VEGF action, was then developed by Genentech for use against colorectal and lung cancer.  The same Genentech inventor also showed (about 12 years ago) that patients with macular degeneration also have high levels of VEGF, in this case near the retina, which led to the development of Lucentis®, another antibody-based drug.

Dr. Levinson pointed out that, despite this coincidence of disease etiology (i.e., inhibiting VEGF as a way to prevent unwanted vascular proliferation), bringing Lucentis® to market required two years of experimental work to improve binding affinity to VEGF, reduce the molecule’s size and make it noninflammatory.  In addition, the drug had to undergo a full regulatory review (Phases I, II and III of the Food and Drug Administrations IND/NDA approval process), and was not approved for use in treating AMD until June 30, 2006.  Dr. Levinson also noted that the Phase III clinical trials for Lucentis® were, in his words, "the most expensive clinical-development program Genentech ever undertook," costing $40,000 – 45,000 per patient.

In Dr. Levinson’s view, the cost of Lucentis® is the result of all these factors, and as such is fully justified.  He also questioned the wisdom of spending the upwards of $50 million it will cost to do the NEI trial, in view of a finite U.S. R&D budget and the overwhelming number of other diseases having no or ineffective treatments.  Finally, he disputed allegations that some patients did not have access to the more expensive Lucentis®, citing coverage by major health insurers and the company’s own drug purchase assistance programs.

Dr. Levinson’s points are well-taken, but in the current climate it will be hard for his comments to change many minds.  Genentech is faced with defending a situation where its drugs, both Lucentis® and Avastin®, are two of only three drugs effective for treating AMD.  (The other is Macugen, sold by (OSI) EyeTech, Inc., which has a far smaller share of the market).  As Dr. Levinson acknowledged, "[t]his is a disease that over the course of days you can go from 20/20 vision to losing your eyesight.  It’s very, very quick, and once you lose your vision, it’s gone and you will probably never get it back."  In addition, neither drug cures AMD but merely stabilizes it, preventing the condition from worsening in many patients.  As a consequence, the drug must be administered like insulin or other maintenance drugs.  At a cost of $2,000/dose and a once-a-month dosing schedule, the cost to treat the half-million "wet" AMD patients in the U.S. with Lucentis® is greater than $10 billion per year.  Avastin® treatment is cheaper because a vial of it costs less ($600/vial) and each vial yields more doses, according to Dr. Edward Chaum, Plough Foundation Professor of Ophthalmology, University of Tennessee (as previously reported in Patent Docs).

Genentech’s decision will do little to either resolve the controversy (which includes assertions by the company that Avastin® treatment entails significantly higher risks of side effects including stroke), nor diminish the anger in the retinal ophthalmology community over the company’s stance.  Nor will Genentech’s decision not to support the NEI study inhibit these ophthalmologists from off-label use of Avastin® for treating AMD.  All the decision will do is limit the comparitors between Avastin® and Lucentis® treatment to anecdotal evidence from off-label Avastin® use, and give additional ammunition to those who unfairly ignore the realities of drug development by focusing on the purported avarice of the innovator drug companies responsible for developing new drugs.  It is not in the public interest to frame the debate in this way, but neither is that interest served by Genentech’s refusal to support the NEI’s study and conform its behavior to that study’s conclusions.

For additional information on this topic, please see:

• "Retinal Specialist on the Avastin®/Lucentis® Controversy," February 23, 2007
• "Lower Doses of Genentech’s Avastin® Effective in Treating Lung Cancer," February 23, 2007

    By Christopher P. Singer —

Last Thursday, the Biotechnology Industry Organization (BIO) published a white paper entitled: "The Myth of the Anticommons."  The paper, authored by Dr. Ted Buckley (BIO Director of Economic Policy), asserts that there is a lack of any strong theoretical or empirical data which supports the theory of the "tragedy of the anticommons."  The basic notion behind this theory is that a system which allows for "over-patenting" stifles, rather than promotes the advancement of downstream technology, because the patenting of upstream technology increases transactional costs and induces more anti-competitive strategic behavior.  Dr. Buckley sets forth some compelling arguments as to why, nearly a decade after Heller and Eisenberg introduced the tragedy of the anticommons to the public (Heller and Eisenberg, 1998, "Can Patents Deter Innovations?  The Anticommons in Biomedical Research," Science 280: 698-701), there appears to be no actual manifestation of this theory in the biotechnology industry.

After providing some general background on the economics of the patent system and the anticommons theory, Dr. Buckley begins his argument by first examining the theoretical underpinnings of the theory.  While he acknowledges that the anticommons approach is elegant and compelling, the focus of Dr. Buckley’s argument is on how the theory is too simple to apply to a system with the inherent complexity and diversity of biotechnology.  He notes that many of the analogies used to explain the theory are not applicable to biotechnology because the industry does not have the same type of scarcity of resources ("biological commons") that are present in typical geometrical or geographical models (such as toll roads
and waterways).  Dr. Buckley uses several examples to argue that biotechnology lacks such scarcity.  He points to the multiple statin-based drugs that are currently on the market and used to lower cholesterol, the variety of breast cancer drugs in clinical development, and the number of products being developed for the treatment of chronic myeloid leukemia.  These examples, he argues, demonstrate how patents have taught the biotechnology industry to explore alternative pathways to try and solve a common challenge, essentially creating new "real estate."

Dr. Buckley also presents several lines of empirical evidence which, he argues, demonstrates in real economic terms that the anticommons approach may not be relevant to biotechnology.  Because the lead time of a drug product from patent to market is anywhere from nine to twelve years, he presents an examination of several "inputs" that are critical to the production of novel therapeutics.  In particular, there are three inputs that Dr. Buckley believes would be occurring if the anticommons theory was happening:  (1) the amount of R&D would decrease; (2) the number of potential therapies being tested would decrease; and (3) companies and researchers would lobby for a change in policy.  The data Dr. Buckley presents shows a general increase in dollars spent on R&D, an increase in venture capital investment, and an increase in employment in the biotechnology industry.  He also cites to an increase in both the number of investigational new drug (IND) submissions and of biological compounds entering clinical trials as indicators that more potential therapies are being tested (contrary to what the anticommons would predict).  Lastly, Dr. Buckley points to industrial and academic opinion on the state of the patent system to show that there is not a large movement for patent reform from these groups.  He states that BIO (i.e., the biotech industry) has a positive position on maintaining the current state of the patent system and "fundamentally opposes the notion that patents on [a] broad array of biotechnology inventions are hindering innovation."  He also cites to a 2005 study conducted by the National Academy of Sciences that requested opinions from researchers from universities, non-profits, and government labs, concerning patents and whether the system has hindered research.  The results overwhelmingly showed that only 1% of responders had experienced a delay of more than one month because of patents on "research inputs."  None of those responding to the questions indicated that they had abandoned a line of research because of patented technology.

As Dr. Buckley notes, it is impossible to completely dismiss the possibility that the tragedy of the anticommons may manifest itself at some point.  Nevertheless, he makes several convincing arguments as to why it appears that the anticommons may not have applicability to the biotechnology industry.

For additional information on this topic, please see:

• "The ‘Anti-Commons’ Aren’t So Tragic, After All"
• "Science Fiction in The New York Times"
• "The Future of DNA Patenting"