The drug discovery and development process is a difficult one that takes considerable expertise in both the research and business realms. Seattle currently has approximately 103 biotechnology companies, 21 of which are publicly traded. The area also has a number of non-profit research organizations that participate in a variety of efforts to find new medicines. Biotech companies have been operating here for some 30 years now, during which time some 42 companies have either been acquired or gone out of business. So what are the prospects for developing new drugs here in Seattle? To address this question, I thought it might be helpful to look back at the track record of our local biotechs. Just how many drugs have we developed locally?
Deriving an answer to this question turned out to be anything but simple. Some drugs were discovered and developed here, some drugs were discovered elsewhere but were developed for new clinical indications by Seattle companies, and some drugs were simply acquired and then sold by our local biotechs. There are a few other caveats I should point out. A majority of these drugs were developed with the help and financial assistance of big pharma partners. Biotechnology also formed the technological basis for several companies that developed medical devices that went on to become FDA approved and treat patients, as noted below. Finally, I want to acknowledge that there have been a number of successes locally in medical devices, agricultural biotech, diagnostics, and biocomputing software applications. However, my focus today is on drug discovery and development. Let’s take a look back and see where we’ve been:
Seven Drugs Discovered and Developed by Seattle Biotechs
Leukine (sargramostim) was developed by Immunex and was FDA approved in 1991 to stimulate the proliferation of white blood cells in patients recovering from bone marrow transplants. Leukine only captured a small share of the market due to stiff competition from Amgen’s competing drug filgrastim (Neupogen), which was approved a month earlier by the FDA for a much wider clinical indication. Amgen’s purchase offer for Immunex led to the divestiture of Leukine to Berlex, the US subsidiary of Schering AG, for antitrust reasons. Berlex was in turn acquired by Bayer in 2006, who subsequently sold Leukine to Genzyme in 2009.
Enbrel (etanercept) was originally developed by Immunex for use in the treatment of sepsis, but it failed in its clinical trials. While most companies would have buried a failed drug, Immunex resurrected Enbrel by testing it in clinical trials with rheumatoid arthritis patients. Strongly positive results led to FDA approval in 1998. Subsequent clinical trials expanded its use for a number of disorders, including juvenile rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, and plaque psoriasis. Acquiring Enbrel was the primary reason Amgen purchased Immunex in 2002. Enbrel went on to become the best selling biologic drug in the world, with worldwide sales in 2008 of $7.4 billion. Amgen’s purchase of Immunex also brought on board the monoclonal antibody that would become panitumumab (Vectibix), and prevented a nasty patent war between the companies over intellectual property that led to the newly approved osteoporosis drug denosumab (Prolia).
Cialis (tadalafil) was initially discovered by Glaxo Wellcome (now Glaxo SmithKline) as part of a Glaxo/Icos partnership. Glaxo abandoned its interest in tadalafil because it didn’t fit into Glaxo’s corporate strategy at the time. Icos then partnered with Eli Lilly to fund a joint venture to develop and commercialize the molecule; it was FDA approved in 2002 for the treatment of erectile dysfunction. Eli Lilly went on to acquire Icos in 2007 and sadly closed down the company. Cialis was later approved for the treatment of pulmonary arterial hypertension in 2009.
Orencia (abatacept) is a fusion protein that inhibits the activation of T cells and is used to treat rheumatoid arthritis in patients not responding to anti-TNF therapies. It received FDA approval in 2006. What is not well known is that Orencia arose from work done here in Seattle at the BMS Pharmaceutical Research Institute. BMS closed down the Seattle branch of its Research Institute in 1997, and the development work was transferred to other parts of Bristol-Myers Squibb.
Zymogenetics’ Recothrom (recombinant human thrombin) was approved by the FDA in 2008 for the topical treatment of surgical bleeding. It was developed as part of a safety-driven trend in biotechnology in which recombinant human proteins have replaced ones that used to be purified from either animal or human sources. Other examples include insulin, hemophilia proteins, and growth hormone. Interestingly, Zymogenetics points out on one of its websites that “the Company has contributed to the discovery or development of six recombinant protein products currently marketed by other companies. These products have aggregate annual sales of more than $3 billion”. Given the disappointing sales ($30M in 2009) of Recothrom, it’s unfortunate that the company could not have held on to one or more of these other unidentified proteins.
Dendreon’s Provenge (sipuleucel-T) was just approved by the FDA in April of 2010 for the treatment of prostate cancer. Dendreon’s clinical success with Provenge has triggered a tsunami of activity by other biotechs in the area of immunotherapy, which had been out of favor for a long time. It should be noted that Provenge is not a classic drug per se because it is not directly administered to patients. Instead, it is a method of treating a patient’s cells outside of their body, and then reinfusing them to stimulate their immune system.
Amgen’s Prolia (denosumab) was FDA approved in June 2010 for the treatment of postmenopausal osteoporosis; it is also being reviewed by the agency for the treatment of prostate cancer patients who are at high risk of bone fractures. Both Immunex and Amgen invested considerable research efforts into the discovery of a protein, RANK ligand, that plays a key role in the biological process of bone remodeling. This ultimately led to the development by Amgen (after it acquired Immuex) of the monoclonal antibody denosumab, which inhibits the activity of this protein.
New Uses Approved for Three Already Discovered Drugs
PathoGenesis (along with Children’s Hospital in Seattle) developed Tobi, (tobramycin solution for inhalation), for the treatment of Pseudomonas aeruginosa infections in patients with cystic fibrosis. The FDA approved the drug for sale in late 1997. Developing the drug for use as an inhalation therapy for CF was a novel use for tobramycin, which was discovered in 1975. PathoGenesis was subsequently acquired by Chiron in 2000, which in turn was purchased by Novartis in 2006.
Corus Pharma developed an inhaled form of the antibiotic aztreonam lysine for the treatment of bacterial infections in the lungs of cystic fibrosis patients. The discovery of aztreonam dates back to 1982. Gilead Sciences purchased Corus Pharma in 2006 as a result of Corus’s development work with this drug. Gilead went on to win FDA approval in February 2010 for the inhaled form of aztreonam lysine, which is sold under the brand name Cayston.
Immunex began selling Novantrone (mitoxantrone hydrochloride) after American Cyanamid (later Wyeth, now Pfizer) acquired a majority ownership position in Immunex in 1993. The drug had been used since 1987 for the treatment of acute nonlymphocytic leukemia. In 1997, Immunex got expanded FDA approval to use Novantrone for the treatment of pain in late stage prostate cancer patients. Immunex rode the expanded use wave again in 2000, when they received FDA approval to use Novantrone for yet another new indication: to reduce neurological disability and/or the frequency of clinical relapses in MS patients. In late 2002, Amgen sold the U.S. rights to Novantrone for several indications in Serono, who then turned around four months later and sold the rights to OSI Pharmaceuticals.
Two Drugs Acquired and Developed by Seattle Based Biotechs
Corixa acquired Bexxar (tositumomab) by purchasing its developer, Coulter Pharmaceuticals, for $900 million in 2000. Coulter had an agreement with SmithKline Beecham (now GlaxoSmithKline) to share marketing and profits for the drug. The FDA approved Bexxar in late 2003 for the treatment of follicular non-Hodgkin’s lymphoma. Bexxar is a monoclonal antibody linked to radioactive iodine that is directed against the cell surface CD20 protein. Difficulties with the “commercial acceptance” of this difficult-to-administer radiolabled drug led Corixa to transfer Bexxar marketing and development rights to Glaxo in 2004. GlaxoSmithKline subsequently acquired Corixa in 2006, primarily for its vaccine adjuvants (see below).
Vectibix (panitumumab) is a monoclonal antibody that blocks the binding of epidermal growth factor to its receptor. As a result, it slows down the growth of tumor cells that express this receptor. Immunex had signed an agreement in 2000 to co-develop this antibody with Abgenix (who had engineered it) and the two companies were working on it together when Amgen acquired Immunex. Amgen won FDA approval of Vectibix in 2006 for the treatment of colorectal cancer. Amgen later acquired Abgenix in 2006 in order to obtain the entirety of Vectibix revenues as well as eliminate the need to pay royalty payments to Abgenix on their monoclonal antibody denosumab (see Prolia above). In one of the first examples of the utility of cancer biomarkers, it was found that Vectibix did not work in the 40 percent of colon cancer patients who have a mutation in a gene called K-RAS.
Drugs Bought and Sold by Seattle Based Biotechs, But Not Developed Here
Cell Therapeutics acquired Trisenox (arsenic trioxide) by purchasing PolaRx in 2000. CTI received FDA approval for Trisenox that same year for the treatment of the relatively rare disease acute promyelocytic leukemia (APL); there are only about 1,000-1,500 cases in the US per year. Cell Therapeutics wound up selling Trisenox to Cephalon in 2005. This made sense since it was reported that the company spent $100 million on Trisenox during this time, while netting only $67 million in sales.
Cell Therapeutics also purchased Zevalin (ibritumomab tiuxetan) from Biogen Idec in 2007. Like Bexxar (see above) Zevalin is a radiolabeled monoclonal antibody directed against CD20 for the treatment of non-Hodgkin’s lymphoma. Zevalin is coupled to radioactive yttrium, whereas Bexxar is coupled to radioactive iodine. Zevalin had been approved by the FDA in 2002. When sales turned out to be less than hoped for, Cell Therapeutics turned around and sold Zevalin to Spectrum Pharmaceuticals in 2009. Radiolabeled drugs such as Zevalin (and Bexxar) are notoriously difficult to manufacture and administer, which severely limits their sales.
Other Local Biotech Approvals That Were Medical Devices, Not Drugs
The Prosorba Column, developed by Imre Corp, was approved by the FDA in 1987. The column, which consisted of protein A bonded to a bead, was developed to treat patients with idiopathic thrombocytopenic purpura (a bleeding disorder) by removing circulating immune complexes from their blood. Imre moved to San Diego and changed its name to Cypress Bioscience in 1996, and the Prosorba Column went out of production in 2006.
CellPro developed the Ceprate column for purifying blood stem cells so they can be reinfused into patients following chemotherapy; the FDA approved it in 1996. Unfortunately, CellPro lost a patent infringement lawsuit to Becton Dickinson (BD) in 1997 and as a result they were forced to divest their Ceprate column to BD. Gutted, the company went under in 1998. An interesting side note: CellPro’s CEO, Rick Murdock, was one of the first people treated with the Ceprate column following his diagnosis with a rare case of mantle cell lymphoma. This fascinating story was recounted in the poorly written book “Patient Number One,” by Murdock and David Fisher.
Iamin, a hydrogel wound dressing, was developed by Kirkland-based Procyte. It was approved by the FDA in 1996, although not as a drug, but a class I medical device. Iamin is sold as a wound care product, although the company is prohibited from claiming that it is a wound “healing” drug. The active ingredient in Iamin is a tripeptide that is complexed with copper. It is now available over the counter.
Though not technically a drug per se, Corixa helped develop mpl (monophosphoryl lipid A), a vaccine adjuvant that it acquired by purchasing Ribi ImmunoChem Research in 1999. Mpl is an immunostimulatory molecule that boosts the immune response to immunogenic molecules contained within various vaccine preparations. Cervarix, the first vaccine that was developed to treat cervical cancer, was the first vaccine licensed by the FDA that included mpl as a component of an adjuvant (i.e. a substance that enhance an immune response) along with alum. GlaxoSmithKline got the rights to mpl when it purchased Corixa in 2005 (see above).
So there we have it. A total of about 145 biotech companies (existing ones, plus those that were acquired or went out of business) discovered and/or developed a total of 12 drugs to date over a 30 year period. On a decade-by-decade basis, no drugs were approved in the first 10 years (1980-1989), four were approved in the second decade (1990-1999), five were approved in the last 10 years (2000-2009), and already three have been approved in this decade (2010-2019). The rate of FDA approvals for drugs arising from Seattle appears to be accelerating as the industry matures and the number of companies here has increased. The pipelines of the companies still in business are filled with some very promising molecules that are in clinical trials for a variety of medical indications. If and when these get approved, then our overall success rate will go up. Molecules as well as the intellectual property of companies that have been acquired (or gone out of business) may also lead to future drugs that will trace their way back to Seattle. In addition to the 12 drugs discovered or developed here, three other medical biotech discoveries were created and brought to market (Prosorba, Ceprate, and mpl) and two other drugs (Trisenox and Zevalin) were sold by Seattle biotech Cell Therapeutics for a few years each.
Thus, a historical review has Seattle developing about one drug for every 12 companies that are (or were) based here. No company, aside from Immunex/Amgen, was successful in developing more than a single drug during this time period. Of the eight companies that were successful in getting a drug approved, only two, ZymoGenetics and Dendreon, remain independent and based in Seattle. Note also that the sales of these drugs cover a huge range (3 orders of magnitude), from less than $10 million per year to $7.4 billion per year. If the historical trend continues, then 11 out of every 12 of our current companies are likely to never have a drug approved. Given the current economic climate, this seems a reasonable prediction. The success rate for local companies bringing new medicines to market (one in twelve, or eight per cent) is equivalent to the current success rate of drugs making it through the clinical trial process on to FDA approval.
What is abundantly clear is that this is a very tough business. In theory, future drug development prospects should look better than what has been achieved in the past due to the fact that the industry has matured greatly, and companies have better focused their discovery efforts. Having said that, I believe that future successes will depend on three primary factors.
First, researchers must acquire an in-depth understanding of biological processes that are involved in the disease process. Everything flows from the basic and applied research that represents the combined efforts of investigators worldwide. Second, technological breakthroughs are needed that will enable both an understanding of the science as well as a means of converting those insights into innovative medicines. Finally, sufficient financial resources are required to fund these research efforts for an ample length of time, be they public or private. As I have argued previously, I believe the current venture capital funding model is not capable of getting the job done.
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