From living sources: The making of biologics
From July/August 2003 Psoriasis Advance
Seven months ago, Bruce Weiner, a delivery truck drive 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."
Biologics like Enbrel (others approved or that are in development
for treating moderate to severe psoriasis and psoriatic
arthritis include Amevive, Raptiva 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.
"But why is it so expensive?" Weiner asks.
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 promising new treatment options.
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.
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.
Expense
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 ensuring
prescription drug coverage for people with psoriasis
and psoriatic arthritis. For details on how the Foundation
may be able to help you with a claim, please visit the insurance advocacy section.
—Will Morton, Editor
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