Precious Plasma

Transfusion centers used to throw plasma away as though it were extraneous liquid, keeping only the red blood cells. During World War II, researchers discovered that the fluid left over after the red cells had been spun free contained vital proteins, and biochemist Edwin Joseph Cohn developed a method for their large scale extraction. Over the years, the scrutiny of plasma produced many new proteins that could be processed and used as life-saving medical treatments for rare blood diseases like hemophilia. Plasma fractionation is now a $6.5-billion-a-year business and more than a million people receive plasma therapeutics annually.

Until recently, it was a low-profile sector of the high-profile biotech boom. But European outbreaks of bovine spongiform encephalopathy (BSE) and its human derivative variant Creutzfeldt-Jakob Disease (vCJD) have raised concerns about the safety of the global blood supply and plasma-based products. And new regulations threaten to cause shortages in both.

Safety First

The United States, producing 50 percent of the plasma worldwide, is the center of the business, and Aventis Behring, headed by CEO Ruedi Wager, is one of the leading players. Plasma collected in the United States is "basically used everywhere," Wager says. "The reason is that companies in the United States have a higher standard because of FDA regulation and the understanding that the quality and safety of blood products begins with the donors."

In an industry in which body fluids are taken from one person and given to another, regulation and safety are dominant concerns. Which is why Aventis Behring's plasma collecting unit Aventis Bio-Services, based in King of Prussia, Pennsylvania, acquired an additional 45 donor centers in the United States last year. The company now owns and operates 90 centers, 10 of which are in Germany. That means it oversees the safe handling of the material "from the vein of the donor until the final product," says Wager. "It's a huge competitive advantage. You have the plasma data under your own control, and important information does not escape notice. A majority of fractionators buy plasma from other sources, and then they are dependent on those collectors to get the right information."

The global plasma supply is categorized by origin: 60 percent is recovered plasma from volunteer blood donors and 40 percent is source plasma from paid plasma donors. Wager explains the difference from the company's perspective: "Volunteer donors give blood or plasma two, maybe three times a year. They are not really known, they come in at random. But paid donors for source plasma are donating every ten days. You know them well, and you can see if they are not in good shape to donate. They have also a different sense of responsibility because they are questioned each time they donate."

The Process

Plasma collection is a unique closed-system process called plasmapheresis. Whole blood is drawn from the donor, then spun in a centrifuge that separates the heavy red blood cells from the rest of the liquid. A similar process takes place in charitable blood banks. But in plasma centers, the red cells are then returned to the individual. Healthy bodies can replace plasma in about 48 hours, thus allowing plasma-only donors to sell their body fluids as often as twice a week. Whole blood can be donated only every eight weeks.

FDA regulates both types of collection, requiring healthcare workers to determine potential donors' eligibility by asking a long list of questions such as "Have you ever had hepatitis or been exposed to hepatitis?"and "Have you ever had sex with a man who has had sex with a man?" The idea is to identify health and lifestyle risks that may make donors ineligible up front.

After it's collected, the blood is tested for various pathogens. But traditional testing is not foolproof. Often, the only way to detect a viral presence in blood is to look for the immune system's response: specific antibodies. Wager admits, "We know that tests today, even if they are much more refined than before, still need a certain time to react. They react only when you already have antibodies in your blood, and with blood pathogens, that takes days or weeks."

To combat that problem, Aventis has developed an investigational polymerase chain reaction method that allows researchers to replicate the genetic material of the pathogens until the volume reaches the discovery level. Being able to see the actual virus rather than the antibody enables much earlier detection and makes the screening process safer. The PCR test is currently in Phase III clinical trials, and Aventis has other, more sensitive tests in development.

"We were the first company using these proprietary testing processes on all plasma for five viruses-hepatitis A, B, and C; HIV; and parvovirus B19," Wager comments on the company's safety efforts, "even when it was not requested by the regulatory authorities."

New Regulations

One of the biggest concerns now for blood-supply and plasma-product safety is the potential presence of rogue prions, those peculiar proteins that change shape and cause deadly transmissible spongiform encephalopathies (TSEs). "All the evidence we have today says there is no transmission of prions that can cause mad cow disease or vCJD through blood," Wager says. "And because we are a leader regarding quality and safety, that means we have to take it very seriously. And we have invested, and will continue to invest, a lot of money to further understand this issue."

FDA, the Red Cross, the International Authority for the Source Plasma Collection Industry (ABRA) and other organizations are also taking TSEs very seriously. Last year FDA required collection centers to start screening out donors who had spent six months or more in Britain between 1980 and 1996. The agency's new rules, which go into effect early next year, will bar donors who

• have spent three or more cumulative months in Britain during that time period

• have spent five cumulative years or more in France from 1980 to present

• received a blood transfusion in Britain since 1980

• are military personnel or dependents who spent six months or more on a European base between 1980 and 1996.

An even tighter FDA restriction, banning donors who lived anywhere in Europe for five cumulative years or more during the last two decades, will go into effect late next year. The Red Cross has created guidelines for its blood donation centers that are stricter yet. Many in the healthcare industry believe the new rules go too far and will limit the number of donors by 5-10 percent, causing shortages of both whole blood and plasma.

According to an article in Source, a magazine published by an industry association for which Wager is chairman elect, "there are tremendous shortages of plasma-derived products worldwide." In fact, Wager says the number of blood and plasma donors has been in decline for years. But in an ironic twist, the two trends that have caused a shrinking US donor base-economic prosperity and a decrease in citizen charity-are already reversing as a consequence of the September terrorist attack, which could help replace the donors lost to new regulations.

Saving Lives

Even though plasma collection centers are sometimes disdained because of the needy people they attract, they are the necessary first step in creating products with powerful potential. Plasma proteins are used in four main therapeutic areas: coagulation, immunoglobulins, critical care, and wound healing.

The most prominent component in plasma is albumin, which is used as a body fluid replacement in critical care settings and as an excipient in other biological products. More than 120,000 burn victims and 200,000 heart surgery patients a year rely on the use of albumin. Aventis Behring's products, Albuminar-5, Albuminar-25, and Human Albumin, account for about 20 percent of the division's sales.

The company's Gammar line of products is derived from immunoglobulins and issued in the treatment of immunological disorders such as congenital and acquired primary immune deficiency diseases. With daily or weekly treatments, those patients no longer have to spend their lives in isolation or suffer from constant infections. Because immunoglobulins contain antibodies, they are also used as an adjunct treatment for autoimmune diseases like multiple sclerosis and neurological disorders such as Guillain-Barre syndrome.

But the company's most important franchise has one of healthcare's smallest markets: bleeding disorders such as hemophilia and von Willebrand disease. "People with hemophilia previously had to deal with a lot of pain and a very limited quality of life to an age of 25 or 30," Wager says. "Today, with our products, they have the potential to live a normal life and have a normal life expectancy. Unfortunately, the amount of clotting factor is limited, and only part of the world's hemophilia population can be treated today."

Beriplast P and Fibrogammin P, Aventis Behring's wound-healing agents, are popular in Europe as supportive treatments in many surgical situations. Wager explains, " There are two components found in human plasma: thrombin and fibrinogen. If you bring those together, they close a wound very quickly and the hospital stay is potentially shortened." So far, US doctors have been slow to adopt the products, but Wager is optimistic that a second-generation liquid wound-healing agent in development will be easier to use and more widely accepted in the US market.

Plasma Pipeline

"The next product we will launch on the US market and worldwide will be alpha antitrypsin (AAT)," Wager says. "It's for a rare genetic disease that causes an obstructive lung disorder that develops in emphysema. Currently, there is only one product with a limited capacity on the market." FDA has granted AAT fast track status, and Aventis hopes to submit an application next spring. The company is also working with Inhale to develop a version that will go directly to the lungs. That formulation is in Phase II.

Also in clinical trials is MDX-33, intended to treat idiopathic thrombocytopenia purpura. Wager comments: "We have a humanized monoclonal antibody to treat ITP, a rare disease, in which the platelet function decreases and there is more bleeding than with a normal individual. We have found that with this product, which is in Phase II trials, we can restore the platelet function. It may have other clinical applications as well, and we are looking into that."

Another advanced project in the pipeline is the production of a recombinant albumin for patients with a low tolerance for plasma-derived products. According to Wager, the recombinant version will make a better excipient for the manufacturing of other biologicals.

Consolidating Care

In addition to regulatory changes and shortages, Wager predicts the industry is likely to experience a round of mergers as well. "The top four players have a market share of more than 70 percent worldwide," he says. "The majority of the remaining are small, local companies. In most cases, they are heavily subsidized by governments or nonprofit organizations because that was the traditional approach." To compete and generate enough resources to meet ever-increasing quality and safety standards, many of those smaller businesses will have to consolidate.

Aventis Behring intends to be part of that trend. Once it has fully integrated its newest acquisitions, the company plans to expand its plasma collection centers with the goal of collecting 100 percent of the plasma it needs. Today, it is about 85 percent independent, buying only 15 percent from outside sources.

By overseeing the collection of plasma, the company not only seeks to ensure the quality and safety of its products but also has personal contact with almost every donor. Dottie Osborn, a nurse in an Aventis Bio-Services collection centers says, "We watch out for our donors. As part of our rigorous screening protocols, we do a complete physical on the first visit and a complete blood test every four months to check for total proteins to make sure they're not becoming anemic."

Establishing relationships with donors and patients is an important aspect of the company's business culture. "With respect to the hemophilia community, we are discussing a couple of thousand or a couple of hundred of patients per country," Wager says. "It is a very well identified group. Because it is such a small community, we know the patients, and we know how to treat them. We know the patient associations, and we work with them in a close and more dedicated way than in most pharmaceutical markets.

"We have developed a special program that supports patients and gives them information about the safety of products and makes sure they get access to products. We organize camps for kids living with hemophilia. We sponsor a car in the NASCAR races. Kids can sit in the car and talk to the driver. We are really striving to build a community with them."