The Making of Biologics
Seven months ago, Bruce Weiner, a delivery truck driver from Cranston, RI, couldn't lace his boots. His psoriatic arthritis was causing his feet to swell so badly that he was having difficulty walking. Then, he started taking a biologic medication called Enbrel, and things changed quickly. After a couple of weeks, "I noticed my feet weren't swelling and my psoriasis was doing well too," he says. "It's been a godsend."
"But why is it so expensive?" Weiner asks.
Biologics like Enbrel (others approved or that are in development for treating moderate to severe psoriasis and psoriatic arthritis include Stelara and Remicade) represent a major scientific advance not only in psoriasis and psoriatic arthritis treatment, but in medicine in general. It is the complexity of their development that bears the tale of their effectiveness and expense.
The making of a biologic
Who would have imagined that one day people would be using a psoriasis treatment made from Chinese hamster ovary cells? Or that these cells would pump out the drug like miniature factories while floating in a nutrient soup in a bioreactor? It's a far cry from coal tar to say the least.
Biologics are proteins derived from living sources. In a strict sense, they are not "new" drugs—they have been in use for more than 100 years. Vaccines and insulin are considered biologics because they are derived from living sources. Only recently, however, have biologics that specifically target psoriasis and psoriatic arthritis begun to emerge as potentially promising new treatment options.
The first step in the making of a biologic essentially takes place prior to the process at the manufacturing plant. Researchers must first genetically engineer a cell so that it produces the desired protein. This requires inserting a gene—one that has specifically been created by splicing DNA together—into the cell to give it the instructions it needs to begin producing the protein.
Once the cell is producing the protein (the "drug"), scientists encourage the growth of the cell with enzymes until billions of copies of the original cell develop. This "cell line" is frozen and serves as a master cell bank, so future batches are identical when the drug is produced.
The first manufacturing step is to thaw cells from the original cell line and place them into two-story containers called bioreactors. There, they undergo fermentation. The "medium" inside the bioreactor is a delicate balance of nutrients, such as oxygen, nitrogen and carbon dioxide, designed to nourish the cells and encourage the production of the protein.
This stage requires around-the-clock monitoring to make sure the optimum levels of nutrients as well as the proper temperature inside the bioreactor are maintained. In some cases, technicians perform more than 35 tests to ensure the quality of the product.
After approximately two weeks, the protein is "harvested." The soup from the bioreactor is put into purification tanks that separate the drug from the medium. Several additional purification steps take place that remove cellular debris, unwanted proteins, salts, minerals or other undesirable materials. At the end of this process, the product is essentially pure.
In preparation for human use, the drug is processed into its final form by the addition of finishing compounds, such as salt and stabilizing agents. In some cases, such as Enbrel, the product is freeze-dried and all moisture is removed.
Where did biologics come from?
The breakthrough that allowed biologics to be developed took place in the mid-1980s when it was confirmed that interactions among cells involved in the immune system were responsible for triggering psoriasis.
"Researchers realized that if you could block these interactions you could prevent the disease," says Dan Freedman, Ph.D., the program executive who oversaw the development of Amevive for Biogen, a Cambridge, Mass., biotechnology company. (Editor's note: Amevive is no longer manufactured or prescribed.)
From that understanding, researchers at the Dana Farber Cancer Institute in Boston identified an interaction between receptors ("lock and key" molecules on cell surfaces that allow them to communicate) on two key cells that play a role in triggering psoriasis. The next step was the development of a gene—literally experimenting by splicing bits of DNA together—that would produce a protein to block this interaction.
Working collaboratively, Freedman said, researchers at Biogen and Dana Farber did just that: developed and isolated a gene that they eventually successfully inserted into a Chinese hamster ovary cell, which indeed produced the desired protein. The generic name of the drug is "alefacept," partly because the drug targets receptors.
Other biologics prevent interactions between other cells involved in the immune system response that leads to psoriasis and psoriatic arthritis. These drugs are thought to be safer than certain other systemic (oral or injected) drugs because they prevent only specific interactions among cells, rather than cause system-wide suppression of the immune system.
For all, early development took years, and it was only the beginning.
While companies won't divulge the costs of manufacturing their drugs, they do maintain one of the biggest reasons biologic drugs are so expensive is that the costs of developing the drugs is astronomical. The companies are trying to recoup the costs of testing the drug in clinical trials and submitting it to the U.S. Food and Drug Administration (FDA).
Development includes conducting phase I, II and III studies to establish the safety and effectiveness of the drug, as required by the FDA. According to the pharmaceutical Research and Manufacturers of America (PhRMA), a lobby group for the drug industry, the cost alone of phase II and III studies is $169 million.
Between the time researchers begin to develop a new prescription drug and the time it receives approval from the FDA, a company will spend approximately $802 million over the course of 10 to 15 years, says the Tufts Center for the Study of Drug Development.
On the other hand, according to Public Citizen, a nonprofit consumer advocacy organization that claims it used the same data as PhRMA to add up the costs, after taxes, the actual cost for research and development of a new drug is approximately $110 million.
Nonetheless, according to PhRMA, only three out of every 10 marketed drugs produce revenues that match or exceed the average research and development costs; of every 5,000 medicines clinically developed, only five on average make it to the clinical trial phase of testing and only one of these five is eventually approved for patient use.
The National Psoriasis Foundation is dedicated to improving the safety and affordability of psoriasis and psoriatic arthritis treatments. Learn more »