Enjoying wine and cheese is nice, but what else can we do?
Last weekend, I indulged with a friend on a young Californian Cabernet Sauvignon and some cheese. The world of wine is fascinating: tracing the provenance of each bottle, you discover a trove full of rich stories and science. The bottle is an embodiment of its terroir  and viticulture, melded with the local history and the winemaker's philosophy.
Conceptually, making wine is simple. After cultivating and harvesting the grapes, the winemaker prepares the must . Then the magic happens when the invisible yeast cells perform fermentation, which transforms the sugar in the grape juice into alcohol. From wine to kimchi, fermentation, a primitive form of biotechnology, is culturally universal. For millennia, humans have been harnessing the power of microscopic cells, using yeast and bacteria, to produce tasty drinks and food. Then what else can we produce with biology, beyond wine and cheese?
A biologic or biopharmaceutical is any drug produced using biological sources. The history of extracting therapeutics from biology is long, but the first story most people are familiar with would be penicillin, which was isolated from a fungus by Alexander Fleming in 1928. Cells are equipped with sophisticated molecular foundaries, but it had been unimaginable to manipulate cells to produce custom designed molecules. All of this radically changed in 1970s with the recombinant DNA revolution, allowing bioengineers to design and produce custom molecules through cells. But why do we want to use living cells instead of the conventional method—a series of chemical reactions—to synthesize pharmaceuticals?
A picture showing a small bioreactor. Life is fragile, so many conditions (temperature, concentration, nutrients, etc.) should be precisely controlled for efficient production.
The mechanism behind many conventional small molecule drugs such as ibuprofen is inhibition. Imagine the drug as the key and the disease process you want to stop as the door. For example, when you sprain your ankle (ouch!), your body starts a cascade of responses, which includes the cyclooxygenase (COX enzymes). Now if you take an ibuprofen (the key), it will lock the door (the COX enzymes) to subdue the pain signaling. As a drug developer, you simply need to find a new key that locks only the problematic doors. However, finding such key is difficult because there are countless doors in the human body and many doors have similar keys. When the key locks some unintended doors, the side effects occur. One solution is making a more complicated key to increase the specificity, but this large key would be too complex to be chemically synthesized. This is why we leverage the intricate molecular machinery of living cells.
Biologic is paving many new paths for treating devastating conditions such as autoimmune diseases like rheumatoid arthritis and multiple sclerosis, diabetes, previously untreatable cancers, genetic disorders, and infections. However, given the costly development and manufacturing, it typically comes with a steep—or some even say exorbitant—price tag. So how can we ensure that many people can benefit without affecting the financial sustainability of the healthcare system?
Originally developed by Boots in the 1960s, ibuprofen was the first over-the-counter nonsteroidal anti-inflammatory drug (NSAID) in the US and the UK. It quickly became a successful product garnering much profit, but what happened after the patent expired?
Developing a new drug is a daunting endeavor, costing more than a billion dollar over a decade of stringent research and testing. Therefore, to promote R&D, the original innovator gets a market exclusivity. After the patent expires, other companies can manufacture and sell essentially the same (chemically identical active ingredients) drug known as generic drug through a relatively simplified regulatory process. Though the margin would be lower, the generic producers can still profit since there is no initial R&D and regulatory costs. This ultimately benefits the patients since the competition, with many new players in the market, reduces costs .
Before approving generic drugs, there are two details to iron out. The first is establishing the equivalency. How do we make sure a generic is equivalent to its original drug? Here the FDA summarizes some key 10 points on the approval process for generic drugs; in a summary, it should have the identical active ingredients and the same clinical benefits and risks. This means that a patient should be able to take the original drug one day and take a generic one on another day. The issue second is naming. If each generic carries its own brand name, potential inefficiency and mixups can happen (e.g. ibuprofen has a plethora of brand names). Especially when the drugs are interchangeable, it makes sense to assign a single name, which is resolved by naming standards like International Non-proprietary Name (INN) and United States Pharmacopeia (USP).
Even though the exact ingredients are known, copying a bottle of wine would be an insurmountable challenge—unless you have the same vines, the exact plot of land, and all the specific viticulture and winemaking knowledge. Likewise, replicating a biologic is not possible unless you have the master cell bank and the extensive manufacturing data, which are not available to the public even after the patent expiration. Even if another manufacturer successfully reverse engineers and replicates a biologic, the drug will not be structurally identical to the innovator's original biologic; it'll be highly similar or almost identical. This means that the small molecule generic regulatory framework cannot be used for biologic. So how do we regulate?
When the Affordable Care Act was legislated, the Congress also passed the Biologics Price Competition and Innovation Act of 2009 (BPCIA 2009) introduced by Senator Edward Kennedy, authorizing the FDA to approve biologic replicas, also known as biosimilar (also see 42 U.S. Code § 262). The standards are outlined under subsection (k). First, the biosimilar should be, well, biosimilar, which should be supported by analytical, animal, and clinical studies. Second, the biosimilar should have the same mechanism as the innovator's original. Third, it should be used to treat the previously approved conditions. Fourth, the dosage and the route of administration should be the same. Fifth, it should be "safe, pure, and potent." One notable part is that a biosimilar is not a generic (the original/reference biologic ≠ the biosimilar), thus not interchangeable. This means that the regulatory agencies and the companies should keep an eye on the clinical results, and switching which drug to administer should involve a clinician. With the regulatory framework in place and many biologic patents expired recently or expiring soon, a wave of biosimilar is expected in the near future.
Wine and biopharmaceutical might seem totally unrelated, but both liquid potions share the same principle: manipulating the microscopic organisms to produce useful products. Well, I enjoyed the wine. It was smooth and fruit forward with a hint of mint—probably enhanced by the conversation and the music. As I reminisce about the evening with the purple potion, the future of medicine seems bright with biologic, elixir.
the collection of environmental factors in which a wine is produced ↩︎
pressed grape juice with pomace (stems, seeds, and skins) ↩︎
penicillin is still being used, though many bacteria have developed resistance ↩︎
some say that making a conventional drug is like folding a paper airplane while manufacturing a biologic is like building a Boeing 747 ↩︎
some even costing several hundred thousand dollars per patient per year ↩︎
Stewart Adams, the inventor who lead the ibuprofen team, initially tested it for treating his hangover https://www.telegraph.co.uk/news/health/3351540/Dr-Stewart-Adams-I-tested-ibuprofen-on-my-hangover.html ↩︎
generic costs about 85% less than the original https://www.fda.gov/downloads/Drugs/ResourcesForYou/Consumers/BuyingUsingMedicineSafely/GenericDrugs/UCM575213.pdf ↩︎
in the U.S. from 2007 to 2016, $1.67 trillion cost saving thanks to generic. https://accessiblemeds.org/resources/blog/2017-generic-drug-access-and-savings-us-report ↩︎
ibuprofen has 33 atoms. some biologics have ~30,000 atoms, which means replicating at atom-to-atom/bond-to-bond level is intractable. ↩︎
biosimilar approval is also summarized in https://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/TherapeuticBiologicApplications/Biosimilars/UCM581309.pdf ↩︎
paragraph (4) of BPCIA sets the standards for establishing interchangeability. First, "the same clinical result." Second, "the risk in terms of safety or diminished efficacy of alternating or switching ... is not greater than the risk of using the reference product without such alternation or switch." ↩︎
unlike conventional drugs (pills), biologics are typically kept in liquid buffer and administered through infusion/injection. ↩︎