Could you recreate your favourite restaurant meal at home? Imagine the challenge of getting that meal to go and receiving no recipe, no ingredient list; just the final dish that you get to taste, study, and reverse-engineer. What are its ingredients? How do you cook them? What’s in the sauce? Which fat did they use? Is there MSG in there to enhance the umami flavour?
This is the challenge facing pharmaceutical companies that want to market biosimilars. Pharmaceuticals used to be pretty simple in structure, which means that when their patent expired, generic versions of them could easily be synthesized by others. But when drugs are being created by living cells, making copies of them becomes a lot more convoluted.
Welcome to the era of biologics and biosimilars.
Change of plan
The word “biologic” is a hard one to pin down, as it has shapeshifted over the years. In its traditional definition, it encompasses the oldest medicines we have used: plant and animal products revered for their real and alleged medicinal properties. It also includes the daily multivitamin supplement many take (but may not need).
This word, “biologic,” was first documented in 1912, and it would retroactively be affixed to an important act of the American Congress. You see, when scientists began to make more formal use of the biological world to treat diseases, they were doing so free of regulations. This could easily lead to batches of biological medicine becoming contaminated with dangerous substances. In 1901, thirteen children received a diphtheria antitoxin that had been made from the blood of a horse named Jim. Unfortunately, Jim had been infected with tetanus, which means the antitoxin was tainted with tetanus, which resulted in the death of all thirteen children.
Similar tragedies and the risk of contaminated vaccines led to the creation of standards for the manufacturing of viruses, sera, toxins and vaccines in the United States, an act that would later be renamed the “Biologics Control Act” of 1902. This paved the way for the eventual creation of the Food and Drug Administration.
It wasn’t until the 1970s, however, that we saw the modern use of the word “biologic.” Prior to that, drugs were small molecules that could be synthesized in the lab by stringing together the right chemical reactions. Acetylsalicylic acid (ASA), for example, commonly known by its trade name of Aspirin, is made up of only 21 atoms. When the patent that grants exclusivity to the maker of a small molecule drug expires, it is relatively easy for a competitor to make a copy of it. In the case of ASA, you can start with phenol, and in four steps, you have transformed it into sodium phenate, sodium salicylate, salicylic acid, and finally acetylsalicylic acid. Easy peasy.
In 1976, scientists engineered the bacterium E. coli to produce insulin for them. While a headache can be treated with a mere 21-atom molecule like ASA, the management of diabetes required the 788-atom insulin molecule. Harder to achieve using chemistry, easier to let biology have a go at it. This way of getting a living organism to make a therapeutic molecule was approved in 1982 and is widely regarded as the beginning of the biotechnology revolution.
Modern biologics, then, are substances that are specific kinds of drugs. They have a biological origin, meaning they are made by living things. They are processed by humans. And they are more complex than your average drug like ASA. Often, they are made up of tens of thousands of atoms.
So how do you get a living organism to start making a molecule, like a protein, that it normally does not make and which you want to harvest for therapeutic use? If you have a protein of interest in mind (because you know that it would interrupt a disease process inside the human body like a finger interrupting the sequential fall of a row of dominos), you find the gene that codes for this protein. You isolate this gene. You insert it inside a vector, which is a tiny vehicle for this gene. You bring the vector carrying the gene inside a cell, for example the bacterium E. coli. Essentially, you have entered a fully operational factory and given the personnel there a new plan. On top of the shirts and pants it normally makes, the factory will now also be producing masks. So now the cell is making all of its regular proteins, but also insulin, or growth hormone, or an antibody that can be used to treat rheumatoid arthritis, or psoriasis, or a certain form of cancer.
These cells are cultured in large numbers in massive bioreactors, and the therapeutic protein they have been coaxed to produce is isolated from them, purified, analyzed, and formulated so that it is ready for injection or drip infusion, the most common routes of administration, as these large biologics are typically broken down by our digestive system and can’t be given by mouth.
Modern biologics have changed the face of medicine. Adalimumab (also known as Humira), an antibody used to treat a variety of autoimmune conditions, is the second best-selling pharmaceutical worldwide, only recently dethroned by Pfizer-BioNTech’s COVID-19 vaccine. As revolutionary as biologics have been to the treatment of diseases, they have come with a hefty price tag. For people who need to take a biologic drug regularly, the cost ranges between $3,000 and $58,000 every year. In fact, the price of biologics is, on average, 22 times that of their non-biologic counterparts. A bit of competition would lower the price, but making a generic of a biologic when the patent expires turns out to be, well, technically impossible.
The process is the product
Adalimumab, mentioned above, was sold by a single pharmaceutical company for a while. But right now, since the patent has expired, you can get adalimumab from five other sources, all approved by Health Canada. Adalimumab is not alone. Other biologics have also been recreated by other companies and approved by regulatory agencies, starting with human growth hormone approved in Europe in 2006. These are not generics. They are known as biosimilars.
Producing a generic drug like ASA can take a company three to five years and costs them USD 1-5 million. By contrast, developing a biosimilar takes eight to ten years and costs upwards of USD 100 million. That is because a biologic is like a fine-dining meal. You get it to go and study it at home, from every angle, trying to recreate it. And if you don’t get the balance of herbs, spices, and flavour enhancers just right, it won’t be the same.
When biologics are assembled inside of living organisms, the molecular machinery can add a few sprinkles and flourishes to them. These are known as post-translational modifications. That phrase comes from the fact that DNA is transcribed into RNA, which is translated into a protein. When that protein is then changed in small ways, that’s a post-translational modification. The cell can stick a sugar molecular on top of it or a fat molecule to the side of it. It can add a few phosphate groups or alter a couple of side chains. Two proteins issued from the same gene may thus have tiny differences that are not easily detected. They are not identical; they are highly similar. (It is important to note here that these modifications can also happen between batches of a biologic within the same pharmaceutical laboratory.)
A pharmaceutical company working on reverse-engineering a biologic that is now off-patent has to recreate the conditions in which this biologic was originally produced, but just because the patent has expired does not mean the original company releases its recipe books. Thus, the company interested in marketing a biosimilar must test it in a myriad of ways to make sure that, despite any post-translational modification their version has and which the original may not have had, it behaves the same in patients.
This is why a common phrase in that business is “the process is the product.” Adalimumab is not just the antibody. It is the way in which this antibody was made in the lab: the cell system that was used, the temperature, the pH, the food that was given to those cells, the specific ways in which the antibody was isolated and purified. Even the type of metal used in the syringe needle can have a negative impact on the drug. When you buy coq au vin in an upscale French restaurant, you’re not just paying for the dish, but for the expertise that has led to its creation, modification, and presentation. All of that is part of the experience.
Studies have to be done on a biosimilar before it can be approved to make sure it is as close to the original—known as “the reference”—as possible. It has to be tested in healthy volunteers to make sure their immune system deals with it well. It also has to be tested in people with the disease and compared to the reference. Only then can a regulatory agency decide to approve it or not.
Because the process for making a biologic and its biosimilar is both delicate and intricate, it presents additional risks compared to the manufacturing of small molecule drugs. Think of a chef preparing Japanese pufferfish for consumption. If they are sloppy, the consequences can be deadly due to the fish’s toxin. Biologics can easily become contaminated during production, which requires added scrutiny. Small changes in the recipe can lead to proteins clumping up, degrading, or losing their structure. These differences can render the drug less effective and it can also trigger undesired immune reactions.
In a healthcare system burdened by the astronomical price tags of reference biologics, biosimilars offer the promise of reduced costs, but only up to a point. According to a 2019 paper on the topic, the price difference between a small molecule drug and its generic equivalent can go up to a whopping 80%. For biologics, however, it sits between 15 and 30% right now. Biosimilars are expensive to make. And because they are highly similar but not identical, they raise ethical questions that generics typically don’t.
Can a pharmacist replace your biologic prescription with a biosimilar when it becomes available without telling you? Should a doctor be encouraged to switch you to a biosimilar in order to help bring costs down? Because biosimilars are not generics, important questions remain and jurisdictions must grapple with them.
There is another complication here as well: terminology. Biosimilars have aliases: subsequent entry biologics, follow-on biologics, and similar biotherapeutic products. Then there are biobetters, which are biologics that have been significantly and consciously modified for the sake of improvement, like when a chef builds on an existing dish and makes it even better. And none of these should be confused with bioidentical hormones, a hazy marketing term that sounds scientific and natural but isn’t, and which usually consists in hormones extracted from plants and further manipulated, meant to help with menopause but which are actually poorly studied. Given the buzz around all things “bio,” it’s not surprising to see the prefix used as a pseudoscientific halo.
Times change and so do the drugs we use. Pharmaceutical companies were originally offshoots of the textile and dye industries, using their growing understanding of chemistry to transform small molecules through a series of reproducible chemical reactions. Now, many of these companies are harnessing the complexity of living cells to engineer colossal molecules with very specific targets inside the human body, allowing these biotechnological marvels to help manage diseases that otherwise were hard to treat.
We have breathed new life into the world of pharmaceuticals.
Take-home message:
- Biologics are specific kinds of drugs that are made by living things, processed by humans, and are often bigger and more complex than an average drug, like Aspirin
- Biologics can be made by finding the gene that codes for a therapeutic protein of interest and introducing it inside a living cell, which will then use its molecular machinery to produce this protein, which can then be isolated, purified, and made ready for administration
- Because of how complex the manufacturing of biologics is and the tiny modifications that living cells can make to these biologics, it is not possible to make identical copies of them when patents expire, but companies can develop biosimilars that are highly similar and can be shown to be as safe and effective
