The History of Drug Discovery and Development in Seattle
Drug discovery and development is a difficult process that takes considerable expertise in both the research and business realms. Seattle (and the rest of Washington state) currently has approximately 120 drug-focused independent biotechnology companies, about 20 of which are publicly traded either in the U.S. or Japan. The area also has a number of non-profit research organizations (e.g. University of Washington; Fred Hutchinson; Children’s Hospital) that participate in a variety of efforts to find new medicines. They often spin off new companies based on the intellectual property that they create. Biotech companies have been operating here for over 40 years, during which time approximately 140 of them have either been acquired, merged, moved out of town, or gone out of business (see my Seattle Biotech Graveyard list). Are there lessons to be learned by studying the history of drug development in Seattle? To answer this question, I thought it might be helpful to look back and examine just many drugs have been discovered and/or developed in Seattle and environs.
Answering this question turned out to be anything but simple. Drug development is not the same as drug discovery. Some drugs were discovered and developed here; some were discovered elsewhere but were developed for different diseases by Seattle companies. Others were simply purchased and then sold by our local biotechs. I’m going to take a generous interpretation here and include all of these different drug development categories in my analysis.
There are a few other caveats I should point out before I dive into the details. First, many of these drugs were developed with the help and/or financial assistance of Big Pharma partners. Second, biotechnology was the technological basis used by several companies to develop non-drug medical products that earned FDA approval, as noted below. I won’t spend much time discussing them. Finally, I want to acknowledge that there have been a large number of successes locally in medical devices, agricultural biotech, diagnostics, veterinary medicine, and biocomputing software applications. However, my focus today is on human drug discovery and development, so I won’t be covering those sub-groups. Let’s take a look back and see where we’ve been, and where we might be going.
Where Do New Drugs Come From?
How drugs are created is a complicated process. Some drugs are discovered and developed by a single company, but more and more this “single actor” pathway has becoming a rarity. Most molecules these days that lead to the development of a drug (or actually become a drug) are discovered in one place, then wind up getting passed around (like respiratory viruses) and are developed elsewhere. The reasons for this are generally financial. Small biotechs are seldom created with sufficient funds for full drug development (which is distinct from drug discovery). They need to raise substantial capital to bring their drugs to market. Financing can be obtained through venture capital investors, stock offerings, collaboration with bigger companies with deeper pockets, or even by being acquired by a wealthier company that can move a drug candidate further down the development pipeline.
Not all drugs that earn FDA approval (meaning they can be sold to the public for a specific use) are newly discovered molecules. Already created drugs can also be repurposed for new uses, gain intellectual property protection for this new use, and then gain FDA approval. This requires running one or more clinical trials that show that an existing drug is effective as a treatment for a disease for which it was not previously approved (a process known as label expansion). FDA approval can also be won by reformulating existing drugs to be administered via a different route, such as inhaled into the lungs, or squirted up the nasal passages. Sometimes existing drugs are combined into a single pill or injection, and that drug combination can than be used for a new purpose, or marketed as being more convenient to take. Seattle area companies have used all of these pathways to bring drugs to market.
Lessons Learned: Earning FDA Approval Is Difficult
The actual rate of FDA approvals for drugs arising from Seattle (number of drugs approved/number of biotech companies) is difficult to calculate. That’s because there’s no official “list” that’s been tracking the number of biotech companies over time. Many people prefer using the term “life science” company, but that phrase is pretty much worthless because it incorporates too many different activities to be useful. The number of existing biotech companies has waxed and waned over time in step with the national economy and investment trends. The current pipelines of some Seattle biotech companies are filled with some very promising molecules that are in clinical trials for a variety of medical conditions. If and when these earn FDA approval, then the overall success rate will go up.
Molecules and intellectual property obtained from Seattle companies (via acquisition or purchase) may also lead to future drugs that will trace their way back to our region. Zymogenetics is the “poster child” for companies whose scientific discoveries wound up earning lots of money not for itself, but for other companies. According to its old 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, the only drug it actually brought to market (it earned only $30 million in 2009, the year before Zymogenetics was acquired by Bristol Myers Squibb), it’s unfortunate that the company could not have held on to one or more of these other unnamed molecules.
Only Immunex/Amgen and Seagen have been successful in developing more than a single drug from scratch. Of the Seattle area companies that were successful in getting a drug approved, only Omeros, Impel Neuropharma, and CTI Biopharma remain independent and based in Seattle (Seagen is in the process of being acquired by Pfizer). Note also that the worldwide sales of drugs in that were discovered or developed in Seattle cover a huge range (over 3 orders of magnitude) of peak year sales, from less than $7 million per year for pixantrone (Pixuvri) to more than $8.78 billion per year for etanercept (Enbrel).
One disturbing pattern that’s become evident is that Big Pharma acquisitions of Seattle biotechs often leads to them being “strip mined,” usually for one particular drug. The remaining assets are dispersed, the company gets shut down, and the staff gets laid off. This happened to the three largest biotechs in Seattle history: Zymogenetics, Immunex, and Icos. History may repeat itself if Pfizer completes its acquisition of what’s currently the biggest biotech in the Seattle area: Seagen. Pfizer has said that they plan to keep Seagen around to create even more new drugs, but Amgen said the same thing about Immunex when they bought it in 2002. They shuttered what was left of the company in 2015.
This “strip mining” trend has led to multiple cycles of boom and bust because when large biotech companies are shut down, our local ecosystem has not been robust enough to absorb more than a small fraction of the laid off employees. The lack of “anchor tenants” (large, well established, and profitable companies that help stabilize geographic clusters of biotech companies) has hurt the development of biotech in Seattle over the years.
Drug Development is a Tough Business
What’s abundantly clear to even the casual observer is that biotechnology is a very tough business. Some drugs will never recover their development costs and become profitable even if they do earn FDA approval. 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, powerful new technologies have been created, and many companies have better focused their discovery efforts.
Future successes for Seattle area biotechs will depend on four primary factors:
(1) First, researchers must continue to acquire an in-depth understanding of the biology that is involved in the disease process. I cannot emphasize this enough. 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 biotech businesses are transformed into A&D (acquisition and development) companies.
(2) Second, technological breakthroughs are needed that will enable the conversion of biological insights into innovative medicines (e.g. turning gene editing technologies into successful treatments for genetic diseases, of which there are hundreds).
(3) Third, significant business acumen is required to turn biologically effective molecules into FDA approvable drugs.
(4) 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.
How Many Drugs Have Been Discovered/Developed in Seattle?
A total of 25 drugs over the past 40-years have been created, developed, or sold here (including label expansions). On a decade-by-decade basis, no drugs were FDA approved in the first 10 years (1980 to 1989), four were approved in the second decade (1990 to 1999), seven were approved in the third decade (2000 to 2009), six were approved in in the fourth decade (2010-2019), and eight have already been approved so far in this decade (2020-2023).
Seven Key Lessons Learned:
1) The vast majority of biotech companies will never develop a drug that will earn FDA approval and be marketed in the US. While they are in business, however, they may provide good paying jobs to the community for as long as they’re around. Their intellectual property may survive and thrive even after they are gone.
2) The development of true blockbusters (usually defined as drugs that bring in revenues > $1B/year) is an exceptionally rare event. Only two drugs developed in Seattle have ever crossed that line: Immunex’s Enbrel (sold by Amgen), and Icos’s Cialis (sold by Eli Lilly), although Immunex/Amgen’s denosumab (Prolia) is closing in on that mark ($992M in sales in 2022).
3) If you are fortunate enough to develop a useful drug that can be used by a substantial number of people (or has the potential to do that) and generate significant revenues, your company will get bought out by Big Pharma. Some companies have hung around for a while after the buyout happens, but the long-term prospects are not good for surviving as an independent company.
4) Big Pharma buyouts are usually a terrible development for the local biotech community. Why? Because history says that will not prosper and grow for the long term. They will be strip mined for any revenue-generating drugs, and most of the folks responsible for that success will find themselves laid off. Our local biotech ecosystem is simply not large or robust enough to absorb even a fraction of the people who get cut loose. This fact has made it difficult to recruit folks to the Seattle area over the years because a layoff here usually means uprooting families to another city for a new job. Failure to develop solid, enduring local companies (i.e. anchor tenants) means that we’ll remain in a continuing cycle of boom and bust. Successful biotech clusters depend on having large, financially strong anchor companies, which is why Boston and San Francisco have thrived nationally as the leaders in biotechnology.
5) Recrafting existing drugs for new uses or to be administered via a new route can be an effective business strategy, as Immunex, Omeros, and PathoGenesis have shown.
6) Getting drugs approved by the FDA is not fully correlated with a company being financially successful. For example, Cell Therapeutics (now CTI Biopharma) has had a number of drug approvals during its long history in Seattle, but it’s been a terrible investment, especially if you bought it at its peak stock price in Sept. 2000. Since then, the stock price declined sharply and is down more than 99.999% despite its most recent drug approval. If you’re going to buy or develop a drug for sale, it helps to have a pretty clear understanding of what sort of sales it might achieve before heading down that road. This can be notoriously tricky to do, and some of the drugs developed here sold so poorly that they were eventually passed on to other companies that weren’t saddled with the development costs. Drug approvals are not always associated with high profits.
7) Label expansion is a winning strategy. Enbrel, Prolia, and brentuximab vedotin (Adcetris) are good examples of drugs that drove sales by winning approval for a number of new indications.
Historical Details of Drug Development in Seattle and Environs
In my previous articles (in 2010 and 2015) about the history of drug development in Seattle, I attempted to classify drugs into categories based on which pathways were used to develop (or purchase) them. However, there are so many sub-variants of this process that it makes classification efforts difficult. This time I’m simply going for a chronological approach, although in each case I’ll endeavor to explain what the development process was. The drug development timeline is also extremely variable. Some drug approvals took place within just a few years of project initiation, while others took decades. The earliest biotech companies were started here in the 1980s, but it wasn’t until the 1990s that the first drugs finally earned FDA approval and were sold to the public. For the purposes of this article, I will count new drug approvals and label expansions as a single drug.
New Drug Approvals 1990-1999
Sargramostim (Leukine) was the first drug successfully developed by Immunex. It earned FDA approval in 1991 to stimulate the proliferation of white blood cells in patients recovering from bone marrow transplants. 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 in 2002 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 in 2018 Partner Therapeutics acquired Leukine, and is still selling it.
PathoGenesis (along with Children’s Hospital in Seattle) developed inhalable tobramycin (Tobi) to treat Pseudomonas aeruginosa infections in patients with cystic fibrosis (CF). The FDA approved the drug for this use in 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.
The process of recrafting an existing drug into one that can be delivered by an inhalation route was not limited to PathoGenesis. Corus Pharma developed an inhaled form of the antibiotic aztreonam lysine for bacterial infections in the lungs of CF patients. Gilead purchased Corus in 2006 and went on to win FDA approval in February 2010 for the inhaled form of the antibiotic, sold under the brand name Cayston. One other well-known example is Afrezza, an inhalable form of insulin developed by Mannkind.
Immunex began selling mitoxantrone (Novantrone) after American Cyanamid (later acquired by Wyeth, which was then bought by Pfizer) acquired a majority stake in the biotech 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. Immunex won FDA approval in 1997 to use it as a treatment for pain in late-stage prostate cancer patients. Immunex rode the expanded-use drug train again when the FDA approved mitoxantrone in 2000 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.
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 adult 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, earning Amgen over $70B.
Amgen’s purchase of Immunex also brought on board the intellectual property that would eventually lead to three different monoclonal antibody drugs: panitumumab (Vectibix), denosumab (Prolia), and tezepelumab (Tezspire); details below. Amgen downsized Immunex’s operations after buying the company, and eventually closed its two research facilities in Washington State in 2015.
Cell Therapeutics Inc. acquired arsenic trioxide (Trisenox) by purchasing PolaRx in 2000. The drug was FDA 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. Teva eventually acquired Cephalon in 2011.
Cell Therapeutics Inc. purchased ibritumomab tiuxetan (Zevalin) from Biogen in 2007. Like tositumumab (see below), ibritumomab tiuxetan is a radiolabeled monoclonal antibody drug. These are notoriously difficult to manufacture and administer, and thus tough to sell. The radioactive antibody is directed against the CD20 protein. The FDA 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.
Tadalafil (Cialis) is a phosphodiesterase-5 inhibitor that was initially discovered by Glaxo Wellcome (later known as GlaxoSmithKline and now simply as GSK) as part of a partnership with Icos. Glaxo Wellcome wound up bailing out on the partnership 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 earned FDA approval in 2003 for the treatment of erectile dysfunction (five years after the FDA approved Viagra for the same use). In 2005, Eli Lilly went on to acquire Icos, but in 2007 Eli Lilly closed down Icos. Tadalafil was later FDA approved for the treatment of pulmonary arterial hypertension in 2009 (under the brand name Adcirca), and for the treatment of benign prostatic hyperplasia in 2011.
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 GSK) 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 human monoclonal antibody cancer drug meant to slow the growth of tumor cells that express receptors for epidermal growth factor. Immunex signed an agreement in 2000 to co-develop this drug with Abgenix (which had engineered it), and the two companies were working together when Amgen acquired Immunex. Panitumumab was FDA approved in 2006 for "the treatment of EGFR-expressing metastatic colorectal cancer with disease progression" despite prior treatment. Amgen acquired Abgenix later that year to grab all of the drug’s revenues (and also to eliminate the need to pay Abgenix royalties on denosumab (Prolia); see below). 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.
Abatacept (Orencia) is used to treat rheumatoid arthritis in patients not responding to anti-TNF therapies such as etanercept (Enbrel) or adalimumab (Humira). Bristol-Myers Squibb received FDA approval for the drug 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. Bristol Myers Squibb later returned to Seattle by purchasing other companies here (see below).
Zymogenetics’ recombinant human thrombin (Recothrom) was FDA approved 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 due to poor sales. After Bristol Myers Squibb acquired Zymogenetics in 2010 (thereby reentering the Seattle market), it entered into an agreement in 2012 that allowed The Medicines Co. to sell Recothrom globally. Bristol Myers Squibb wound up closing down Zymogenetics in 2019.
Amgen’s denosumab (Prolia) was FDA approved in 2010 for postmenopausal osteoporosis in women at high risk for bone fracture. 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. Sales of the drug are approaching $1B a year in 2022.
In 2011, denosumab was also FDA approved for the treatment of bone loss in patients with prostate or breast cancer undergoing hormone ablation therapy (under the trade name Xgeva). The denosumab label was further expanded with FDA approval in 2012 of the drug for men with osteoporosis at high risk for bone fracture. It also earned FDA approval in 2018 for treating glucocorticoid-induced osteoporosis.
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.
Dendreon’s sipuleucel-T (Provenge) earned FDA approval in 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 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. Biovail later acquired Valeant in a reverse merger. Notably, 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.
Seattle Genetics (rebranded as Seagen in 2020) has focused most of its R&D efforts developing antibody-drug conjugates (ADCs), a type of cancer drug that links a guiding monoclonal antibody with a tumor-killing toxin. Its first such drug, brentuximab vedotin (Adcetris), was FDA approved 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. This drug now has achieved a total of seven different FDA treatment approvals, all of which are subsets of classical Hodgkin’s lymphoma, anaplastic large cell lymphoma, or other CD30 expressing lymphomas.
Cell Therapeutics Inc. (rebranded as CTI Biopharma Inc. in 2014) attempted to gain FDA approval in 2010 for its drug pixantrone (Pixuvri), a form of the chemotherapy agent mitoxantrone (see Novantrone above) that the company claimed had fewer heart-related side effects. Novuspharma initially developed the drug, but Cell Therapeutics gained rights to the drug by merging with the Italian company in 2003. The drug was 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 under the brand name Pixuvri.
The conditional approval meant that pixantrone was required to complete additional clinical trials to clearly prove the drug’s safety and efficacy. This additional trial was (finally!) completed in 2018; unfortunately, it showed that the drug failed to improve progression-free survival versus a commonly used combination regimen of Rituxan and bendamustine. The drug was licensed to the French drug company Servier in 2019, although their plans for it are unclear. It appears that Pixuvri won standard (not conditional) marketing approval in Europe in 2019 despite its failure in the confirmatory trial.
Omeros’s Omidria earned FDA approval in 2014 for use during cataract and lens replacement surgery, but the drug wasn’t launched until early April 2015. 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. Syntex originally developed Ketorolac 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. Omeros sold the rights to Omidria to Rayner Surgical in 2021 in order to secure a long-term financial stream.
In 2020 Seagen earned FDA approval for tucatinib (Tukysa), a twice-daily pill meant to treat HER-2 positive breast cancer. It’s approved for use in patients with aggressive metastatic disease that has spread through the body and has resisted several other medications. Nearly half of the 600 women in the trial had breast cancer that had spread to their brains; the drug cut their risk of disease progression in half. In early 2023 it earned a label expansion for treating patients with a specific type of HER2-positive colorectal cancer in combination with Roche’s Herceptin.
Seagen also won a second FDA approval in 2020 for tucatinib. It was approved for use in combination with trastuzumab (Herceptin) and capecitabine (Xeloda) to treat metastatic HER2-positive breast cancer or locally advanced HER2-positive disease that can’t be completely removed with surgery after the cancer has been treated with at least one anti-HER2 medicine.
Tucatinib is not an antibody-drug conjugate. Rather, the drug is a selective tyrosine kinase inhibitor for HER2, the same protein targeted by the blockbuster Herceptin. Tucatinib was originally developed by Array BioPharma, who licensed it to Cascadian Therapeutics (formerly known as Oncothyreon until 2016). Seattle Genetics bought Cascadian Therapeutics for $614 million in 2018, which is how they acquired the rights to this molecule.
Alder’s eptinezumab (Vyepti) was the fourth FDA-approved medicine in a recent run of new drugs aimed at preventing migraines. It’s why Lundbeck spent $2 billion acquiring Alder in 2019; the drug was FDA approved in 2020 for the prevention of migraines in adults. All of the these migraine drugs are monoclonal antibodies that block calcitonin gene-related peptide (CGRP), which is believed to dilate blood vessels in the brain and cause pain. The big hope and promise of this particular antibody is that its quarterly IV infusion dosing schedule can match or beat (in terms of clinical benefit) the other drugs that are dosed as subcutaneous injections every month. Lundbeck hopes that patients will prefer this less frequent dosing regimen. Competitors include Amgen and Novartis’s Aimovig, Eli Lilly’s Emgality, and Teva’s Ajovy.
Seagen (along with partner Astellas Pharma) earned another FDA approval for enfortumab vedotin-ejfv (Padcev) in 2021. This is another antibody-drug conjugate (ADC), which is Seagen’s core technology. Enfortumab vedotin-ejfv is a monoclonal antibody directed against nectin-4; it was approved for treating adult patients with locally advanced or metastatic urothelial cancer (who have previously received a programmed death receptor-1 (PD-1) or programmed death-ligand 1 (PD-L1) inhibitor), and a platinum-containing chemotherapy in the neoadjuvant/adjuvant, locally advanced or metastatic setting. The drug was initially FDA approved in 2019 under an accelerated approval program based on tumor response rate. Continued approval was contingent upon verification of a clinical benefit in confirmatory trials, which was completed in 2021 from the EV-301 trial.
Seagen also earned FDA approval in 2021 for tisotumab vedotin-tftv (Tivdak), a drug jointly developed with Genmab. The drug is yet another antibody-drug conjugate; this one links a tissue factor-directed antibody with the toxic molecule monomethyl auristatin E (MMAE). The drug binds to and forms a complex with tissue factor on the surface of cancer cells; the cells then take it up and die. It was approved for use in second-line patients with recurrent or metastatic cervical cancer who previously progressed after chemotherapy rather than PD-(L)1 systemic therapy.
Back in 2013, Juno Therapeutics was founded to develop CAR-T therapies directed against lymphomas and leukemias. Initial clinical stumbles eventually led the company to be acquired in early 2018 by Celgene, which in turn was gobbled up by Bristol Myers Squibb in late 2019. The drug that led to Juno being acquired, liso-cel, finally earned FDA approval in 2021. The drug, more formally known as lisocabtagene maraleucel (Breyanzi), is a CAR-T therapy that targets CD19 and is used to treat diffuse large B cell lymphoma in patients who have previously received two prior rounds of systemic therapy. It became the third CAR-T treatment to reach the US market, after axicabtagene ciloleucel (Yescarta) from Kite/Gilead and tisagenlecleucel (Kymriah) from Novartis. A second CAR-T developed by Juno, orva-cel, which was targeting BCMA in multiple myeloma, was written off by BMS in Feb. 2021 for competitive reasons in the crowded BCMA CAR-T cell space.
Juno may have come in third place in the US CD19 CAR-T race, but its joint venture in China is doing better. JW Therapeutics, which is named for co-founders Juno and WuXi AppTec, received the second-ever CAR-T approval by China’s National Medical Product Administration. This came just weeks after the approval of Yescarta by Fosun Kite, another joint venture between Kite and Shanghai Fosun Pharmaceutical.
JW Therapeutics CAR-T drug, relmacabtagene autoleucel, (Carteyva), was approved in China in 2021 to treat relapsed or refractory large B-cell lymphoma patients who’ve had two or more lines of systemic therapy. Relma-cel was developed using the same platform that was used to create Juno’s liso-cel (now Bristol Myers Squibb’s Breyanzi).
Impel NeuroPharma earned FDA approval in 2021 for its first nasal spray drug dihydroergotamine mesylate (Trudhesa). The drug itself was a well-established therapeutic molecule; what's new here was the delivery method through the nasal passages. It’s prescribed for the treatment of migraines, with or without aura, in adults. This was the second migraine drug developed in the Seattle area, the first being Alder/Lundbeck’s eptinezumab (Vyepti).
Amgen and AstraZeneca’s tezpelumab (Tezspire) won FDA approval in late 2021 to reduce exacerbations in patients with severe asthma. The drug is a monoclonal antibody designed to neutralize the actions of the cytokine TSLP (thymic stromal lymphopoeitin). Immunex discovered TSLP in the 1990s, and Amgen acquired the intellectual property for this molecule when it bought Immunex in 2002. The IP led to the development of the TSLP-neutralizing antibody by Amgen/AstraZeneca [full disclosure: the author of this article is a named inventor on 14 of the patents for Tezspire].
In late Feb. 2022, CTI Biopharma won approval for its drug pacritinib (Vonjo), an anti-inflammatory drug in the category of Jak2 inhibitors. Pacritinib is to be used by patients with myelofibrosis and that also have a low level of blood platelets (about 7,000 patients in the US). It will compete against Incyte Corp’s ruxolitinib (Jakafi) (FDA approved in 2011) and Bristol Myers Squibb fedratinib (Inebric) approved in 2019.
The drug has a complicated history. It was discovered in Singapore by S*BIO Pte. Ltd., and was later acquired by Cell Therapeutics in 2012. To develop the drug, Cell Therapeutics established a partnership with Baxter International in 2013. The drug later became the property of the Baxter spinoff Baxalta. In 2016 CTI regained the rights to pacritinib from Shire, who had acquired Baxalta earlier that year.
Other Local Biotech FDA Approvals That Were Medical Devices, Not Drugs
The FDA approved the Prosorba Column, developed by Imre Corp, 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’s now available over the counter.
Though not technically a drug per se, Corixa helped develop mpl (monophosphoryl lipid A), a vaccine adjuvant (a substance that enhances an immune response)) 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 vaccine Cervarix was the first vaccine licensed by the FDA that included mpl as a component of an adjuvant (along with a second adjuvant, alum). GlaxoSmithKline acquired the rights to mpl when it purchased Corixa in 2005. Cervarix prevents the development of cervical cancer because it contains proteins that generate neutralizing antibodies against two different strains of the human papilloma virus (HPV) that cause the disease. It was pulled from the US market in 2016 after losing market share to Merck’s Gardasil 9 HPV vaccine, which is effective against nine different strains of HPV.
If you’ve made it this far, you should have developed an appreciation of just how difficult the drug development process is. Most efforts (sadly) end in failure. The reasons for this are many, but to restate a key point made earlier, understanding human biology is one of the most difficult undertakings possible. People like to use the phrase “it’s not rocket science” when they want to indicate that something is relatively easy to understand. Rocket science is supposed to be difficult. With all due respect to rocket scientists, compared to human biology, rocket science is easy.
Note: this article is an update of earlier versions I published in 2010 and 2015.