The drug discovery and development process is a difficult one that takes considerable expertise in both the research and business realms. Seattle (and the rest of Washington state) currently has approximately 112 drug-focused biotechnology companies, 17 of which are publicly traded either in the U.S. or Japan. 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 35 years, during which time about 109 of them have either been acquired, merged, moved out of town, 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?
Answering this question turned out to be anything but simple. Some drugs were discovered and developed here, some were discovered elsewhere but were developed for different diseases by Seattle companies, and others were simply acquired and then sold by our local biotechs. There are a few other caveats I should point out. First, most of these drugs were developed with the help and financial assistance of Big Pharma partners. Second, biotechnology formed the technology base that several companies used to develop non-drug medical products that won FDA approval, 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:
Nine Drugs Discovered and Developed by Seattle Biotechs
Sargramostim (Leukine) was developed by Immunex to stimulate the proliferation of white blood cells in patients recovering from bone marrow transplants. It won FDA approval in 1991. Sargramostim 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 to treat a much larger group of patients recovering from chemotherapy. Amgen’s purchase offer for Immunex led to the divestiture (for antitrust reasons) of sargramostim to Berlex, the U.S. subsidiary of Schering AG. Bayer subsequently acquired Berlex in 2006, and then sold sargramostim to Genzyme in 2009. Sanofi acquired Genzyme in 2011 and is currently selling the drug.
Etanercept (Enbrel) was originally developed by Immunex for treating sepsis, but failed in clinical trials. While most companies would have buried a failed drug, Immunex resurrected etancercept by testing it in rheumatoid arthritis patients. Strongly positive results led to FDA approval in 1998, and the drug has since been cleared to treat a number of disorders, including juvenile rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, and plaque psoriasis. Acquiring etanercept was the main reason Amgen bought Immunex in 2002. Etanercept went on to become one of the best selling biologic drugs in the world, with worldwide sales in 2014 of $8.78 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 osteoporosis drug denosumab (Prolia). Amgen downsized Immunex’s operations after buying the company, and eventually closed its two research facilities in Washington state in 2015.
Tadalafil (Cialis) was initially discovered by Glaxo Wellcome (now GlaxoSmithKline) as part of a partnership with Icos. Glaxo wound up bailing out on tadalafil because the drug didn’t fit into its corporate strategy at the time. Icos then teamed up with Eli Lilly to develop and commercialize the molecule; it won FDA approval in 2003 for the treatment of erectile dysfunction. Eli Lilly went on to acquire Icos in 2007 and close down the company. Tadalafil was later approved for the treatment of pulmonary arterial hypertension in 2009, and for the treatment of benign prostatic hyperplasia in Oct. 2011.
Abatacept (Orencia) is used to treat rheumatoid arthritis in patients not responding to anti-TNF therapies like etanercept (Enbrel) or adalimumab (Humira). It received FDA approval in 2006. What is not well known is that abatacept arose from work done here in Seattle at the Bristol-Myers Squibb Pharmaceutical Research Institute. Bristol closed down the Seattle branch of its Research Institute in 1997, and the development work was transferred to other parts of the company.
Zymogenetics’ recombinant human thrombin (Recothrom) was approved by the FDA in 2008 as a topical treatment for surgical bleeding. It was developed as part of a safety-driven trend in biotechnology in which recombinant human proteins replaced ones that used to be purified from either animal or human sources. Other examples include insulin, hemophilia proteins, and growth hormone. Zymogenetics initially partnered with Bayer in 2007 to sell the drug, but regained the rights two years later when Bayer walked away from the deal. After Bristol acquired Zymogenetics 2010, it entered into an agreement in 2012 that allowed The Medicines Co. to sell Recothrom globally.
Dendreon’s sipuleucel-T (Provenge) won FDA approval in April of 2010 to treat metastatic hormone-refractory prostate cancer. It should be noted that sipuleucel-T 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 to battle the prostate cancer cells. Unfortunately, the high cost of the drug, its limited effectiveness, competition from more convenient pills, and the expense of custom generating each patient’s treatment led Dendreon to declare bankruptcy in Nov. 2014. Valeant Pharmaceuticals subsequently purchased Dendreon in Feb. 2015 for $495 million. Dendreon’s initial clinical success with sipuleucel-T triggered a tsunami of activity by other biotechs in the area of cancer immunotherapy, which has been in and out of favor for over a century.
Amgen’s denosumab (Prolia) was FDA approved in June 2010 for postmenopausal osteoporosis. 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 Amgen (after it acquired Immunex) to develop the monoclonal antibody denosumab, which binds to and inhibits the activity of this protein.
In 2010, denosumab was also approved for patients with bone metastases of solid tumors (such as prostate cancer), and who are at high risk of bone fractures. It’s marketed to these patients under the name Xgeva.
Calistoga Pharmaceuticals was one of the first virtual biotech companies, created out of Icos (shortly before that company was acquired by Eli Lilly in 2006) to develop a cancer drug that inhibited the delta isoform of the enzyme PI3 kinase. Gilead bought Calistoga in February 2011 in order to acquire the rights to this drug. Named idelalisib (which Gilead markets as Zydelig), it received FDA approval in 2014 and is used to treat chronic lymphocytic leukemia, relapsed follicular B-cell non-Hodgkin lymphoma, and small lymphocytic lymphoma.
Seattle Genetics has focused most of its R&D efforts developing antibody drug conjugates, a type of cancer drug that links a guiding antibody to a tumor-killing toxin. Its first such drug, brentuximab vedotin (Adcetris), was approved by the FDA in 2011 for patients who have relapsed with Hodgkin lymphoma or who have systemic anaplastic large cell lymphoma. It targets a protein on the surface of the cancer cells known as CD30.
New Uses Approved for Four Already Discovered Drugs
PathoGenesis (along with Children’s Hospital in Seattle) developed inhalable tobramycin (Tobi) to treat Pseudomonas aeruginosa infections in patients with cystic fibrosis. The FDA approved the drug in late 1997. Developing this medicine as an inhalation therapy for CF was a novel use for tobramycin, which was discovered in 1975. Chiron acquired PathoGenesis in 2000, and Novartis in turn bought Chiron in 2006.
Corus Pharma developed an inhaled form of the antibiotic aztreonam lysine for bacterial infections in the lungs of CF patients. The discovery of aztreonam dates back to 1982. Gilead purchased Corus in 2006 and went on to win FDA approval in February 2010 for the inhaled form of the antibiotic, which is sold under the brand name Cayston.
Immunex began selling mitoxantrone (Novantrone) after American Cyanamid (later acquired by Wyeth, which was then bought by Pfizer) acquired a majority stake in the company in 1993. The drug, a type II topoisomerase inhibitor, had been used since 1987 to treat acute nonlymphocytic leukemia, acute myeloid leukemia, and metastatic breast cancer. In 1997, Immunex was cleared to use it as a treatment for pain in late-stage prostate cancer patients. Immunex rode the expanded-use wave again in 2000, when the FDA approved mitoxantrone to reduce neurological disability and/or the frequency of clinical relapses in multiple sclerosis patients. In late 2002, Amgen sold the U.S. rights to mitoxantrone for several diseases to Serono, who then turned around four months later and peddled the rights to OSI Pharmaceuticals.
Omeros’s Omidria won FDA approval in May 2014 for use during cataract and lens replacement surgery, but the drug wasn’t launched until early April 2015, so it’s not clear yet how well it will sell. The drug is a proprietary combination of two well-known medicines, phenylephrine (an alpha1-adrenergic receptor agonist) and ketorolac,(an anti-inflammatory drug that blocks the cyclooxygenase enzyme). It is used to maintain pupil size and reduce postoperative ocular pain by preventing pupil constriction. Ketorolac was originally developed by Syntex in 1989, while phenylephrine has been available for decades in the U.S. and is most frequently used as a decongestant. The scientists at Omeros came up with the idea of combining these two drugs into one solution to prevent problems that can crop up during eye surgery.
Three Drugs Acquired and Developed by Seattle Based Biotechs
Corixa acquired cancer drug tositumomab (Bexxar) 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 tositumomab in late 2003 to treat follicular non-Hodgkin’s lymphoma. Difficulties with the “commercial acceptance” of this hard-to-prepare and administer radioactive drug led Corixa to transfer the drug’s marketing and development rights to Glaxo in 2004. The British firm then bought Corixa two years later, primarily for its vaccine adjuvants (see below).
Panitumumab (Vectibix) is a cancer drug meant to slow the growth of tumor cells that express receptors for epidermal growth factor. Immunex had signed an agreement in 2000 to co-develop this drug with Abgenix (which had engineered it), and the two companies were working on it together when Amgen acquired Immunex. Panitumumab was FDA approved in 2006 to treat colorectal cancer, and Amgen acquired Abgenix later that year to grab all of the drug’s revenues and eliminate the need to pay royalties to Abgenix on denosumab (see Prolia above). In one of the first examples of the utility of cancer biomarkers, it was found that panitumumab did not work in the 40 percent of colon cancer patients who have a mutation in a gene called k-ras.
Finally, Cell Therapeutics attempted to gain FDA approval in 2010 for its drug Pixantrone, a form of the chemotherapy agent mitoxantrone (see Novantrone above) that the company believes has fewer heart-related side effects. The drug was initially developed by Novuspharma, but Cell Therapeutics gained rights to the drug by merging with the Italian company in 2003. The drug was then brought before an FDA advisory committee, which unanimously rejected it for flunking its primary goal in a clinical trial, and for Cell Therapeutics’ inability to recruit more than 140 of the planned 320 patients. The company announced plans to resubmit its application to the FDA but never did. Cell Therapeutics did receive conditional marketing approval in 2012 for the drug in several European countries for patients with multiply relapsed or aggressive non-Hodgkin lymphoma. It is sold under the brand name Pixuvri. The conditional approval means that Cell Therapeutics is required to complete additional clinical trials to clearly prove the drug’s safety and efficacy. If it does not reach this milestone, the drug’s marketing approval may be rescinded.
Other Drugs Bought and Sold by Seattle Based Biotechs, But Not Developed Here
Cell Therapeutics acquired arsenic trioxide (Trisenox) by purchasing PolaRx in 2000. The drug was approved that same year to treat the relatively rare disease acute promyelocytic leukemia; there are only about 1,000 to 1,500 cases in the U.S. per year. Cell Therapeutics wound up selling the drug to Cephalon in 2005. This made sense since it was reported that the company spent $100 million on arsenic trioxide during this time, while netting only $67 million in sales. Cephalon was eventually acquired by Teva in 2011.
Cell Therapeutics also purchased ibritumomab tiuxetan (Zevalin) from Biogen in 2007. Like tositumumab (see above), ibritumomab tiuxetan is a radiolabeled monoclonal antibody drug, which are notoriously difficult to manufacture and administer, and thus tough to sell. The antibody is directed against the CD20 protein. The FDA had approved ibritumomab tiuxetan in 2002 for the treatment of non-Hodgkin’s lymphoma, but when sales turned out to be less than hoped for, Cell Therapeutics turned around and sold it to Spectrum Pharmaceuticals in 2009.
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 in 1997 and as a result was forced to sell its Ceprate column to that company. Gutted, the company went bankrupt 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 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 as a 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 combined 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 boosts the body’s response to immune system-stimulating molecules contained within various vaccine preparations. GlaxoSmithKline’s 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 (a substance that enhances an immune response) along with alum. GlaxoSmithKline acquired the rights to mpl when it purchased Corixa in 2005 (see above).
Sorting Out The Numbers
So there we have it: a total of about 220 biotech companies (existing ones, plus those that were acquired, moved, or went out of business) discovered, developed, or found a new use for a total of 16 drugs over the past 35-years. On a decade-by-decade basis, no drugs were approved in the first 10 years (1980 to 1989), four were approved in the second decade (1990 to 1999), five were approved in the third decade (2000 to 2009), and seven have already been approved so far in this decade (2010 to 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 some Seattle companies are filled with some very promising molecules that are in clinical trials for a variety of medical conditions. If and when these get approved, then our overall success rate will go up. In addition to the drugs discovered or developed here, three other biotech discoveries were created and brought to market (Prosorba, Ceprate, and mpl) and two other drugs (arsenic trioxide and ibritumomab tiuxetan) were sold by a Seattle biotech, Cell Therapeutics, for a few years each.
Molecules and intellectual property obtained from Seattle companies (via acquisition) may also lead to future drugs that will trace their way back to our region. Zymogenetics is the current “poster child” for companies whose scientific discoveries wound up earning lots of money not for itself, but for other companies. According to its website, “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 of Recothrom (only $30 million in 2009, before Zymogenetics was acquired), it’s unfortunate that the company could not have held on to one or more of these other unnamed molecules.
No company, aside from Immunex/Amgen, was successful in developing more than a single drug from scratch during this time period. Of the twelve companies that were successful in getting a drug approved, only Seattle Genetics, Omeros, and Cell Therapeutics (now known as CTI Biopharma) remain independent and based in Seattle. All three companies are publicly traded, and each of them lost money last year. Note also that the worldwide sales of drugs in 2014 that were discovered or developed in Seattle cover a huge range (over 3 orders of magnitude), from less than $7 million per year (Pixuvri) to more than $8.78 billion per year (etanercept).
What’s abundantly clear to even the casual observer is that biotechnology is a very tough business. Some drugs will not recover their development costs and become profitable even if you can get them approved. Looking ahead, future drug development prospects in Seattle (and elsewhere) should be better than what has been achieved in the past. The industry has matured and many companies have better focused their discovery efforts.
Having said that, I believe that future successes will depend on four primary factors:
First, researchers must continue to acquire an in-depth understanding of the biology that is involved in the disease process. Everything flows from the basic and applied research that represents the combined efforts of investigators worldwide. These discoveries are likely to increasingly arise from academia as R&D-based businesses are transformed into A&D (acquisition and development) companies. Second, technological breakthroughs are needed that will enable the conversion of biological insights into innovative medicines. Third, significant business acumen is required to turn biologically effective molecules into FDA approvable drugs. Finally, sufficient financial resources are required to fund each of these efforts for an ample length of time in order to achieve success. The challenges are many, but the prospects for the development of new drugs have never been brighter.