Novo Nordisk Takes on Blood Disorders
`People really need to get perspective," says Marcus Carr, Novo Nordisk’s new vice president of research and the director of the company’s new hemostasis laboratory at the Technology Center of New Jersey in North Brunswick. "In America, we love to complain about everything. But when you really look closely, most of us really have very little reason to complain."
For nearly 40 years, Carr has been immersed in the multifaceted problems surrounding blood clotting. As a physician, a researcher, an educator, and throughout his 30-year career in the Army Reserve, he has experienced, first hand, the practical applications of hematology (the study of the blood and blood producing organs) and forensic medicine. Too much clotting? That can mean thrombophilia, resulting in damage to the legs, coronary artery disease, or even pulmonary emboli. Too little clotting? That can result in hemophilia, potentially complicated by chronic joint deformities or even intracerebral hemorrhaging.
"Those who suffer from hemophilia make up a very special population," says Carr. Hemophilia is an inherited disease and, as a group, hemophiliacs tend to be cheerful non-complainers. "They have to put up with so much, and they really did nothing to bring it upon themselves. So it is very gratifying to be able to help them in some way."
By definition, hemophilia is a group of hereditary bleeding disorders of specific blood clotting factors. With two main types, A and B, it is caused by an inherited sex-linked recessive trait. Women carry the defective gene but generally have few symptoms; men are most dramatically affected by the disease.
Hemophilia is rare: it affects just .006 percent or about 20,000 people in the United States. Once called the "Royal Disease," because it was passed to the crowned heads of Europe through the descendants of Queen Victoria, hemophilia was brought to this country by European settlers.
Bleeding is the hallmark of the disease, with mild cases often going unnoticed until a person undergoes surgery or trauma. Symptoms include spontaneous bleeding, bruising, excessive bleeding from cuts or scrapes, nosebleeds that won’t stop, and swollen and painful joints.
Novo Nordisk has long been known as a world leader in diabetes research and development. But in opening the first hemostasis research facility in the United States, Novo Nordisk is demonstrating that it is taking life threatening blood clotting disorders just as seriously as diabetes.
The company began in the 1920s, when two small Danish companies began producing insulin (which had just been discovered). Nordisk Insulinlaboratorium was founded in 1923, and a year later, Novo Terapeutisk Laboratorium began producing "Insulin Novo." Over the next six decades, these two companies became world leaders in insulin production, hemostasis management, growth disorders, and hormone therapy for women. They merged in 1989, becoming a new company called Novo Nordisk, the world’s largest producer of insulin. It markets its pharmaceutical products in 179 countries, has affiliate offices in 78 countries, operates manufacturing facilities in six countries, and employs more than 22,500 people. In Princeton, the 500-person United States headquarters fronts Route 1 on College Road West.
Last September Carr was named to head Novo Nordisk’s new 30,000-square-foot facility on the second floor of a building at the New Jersey Technology Center, 685 Route 1 in North Brunswick. The laboratory’s opening in February also represents the first real step outside of Denmark for big-time research for Novo Nordisk.
Constructed in 2001 by the New Jersey Economic Development Authority, the building was designed by CUH2A, but the interior was modeled after Novo Nordisk’s pharmaceutical manufacturing facility in Hillerod, Denmark. A central research square is surrounded by offices and laboratories, with a huge skylight in the center and windows instead of walls. "It is the most beautiful facility that I’ve ever seen," says Carr. "It has a big hole in the ceiling so that we can keep our eye on heaven."
Prior to selecting the North Brunswick site, Novo Nordisk made an extensive evaluation of potential areas, including northern California, Boston, and the Research Triangle in North Carolina. "The reason this area was chosen was the old story: location, location, location," says Carr. "The first reason is that 40 percent of the world’s drugs are made right along this highway. The second is that we are already in Princeton so that serves as a support base for this facility. Third: the NJEDA was instrumental in helping us look for various locations in New Jersey, and we worked with them on a financing agreement."
Other decision factors included the area’s highly trained workforce and proximity to a number of universities that could serve as potential collaborators in research and development. "We sit two miles from Rutgers and Robert Wood Johnson," says Carr. "Right down the road is the University of Pennsylvania and the UMDNJ. One of the postulates that we made when putting this together is that we will be able to recruit very highly qualified people much easier."
While Denmark continues to be Novo Nordisk’s home base, it does have its limitations. "Denmark is a small country," says Carr. "I think the total population is about 4,500,000 people. While they have excellent universities and a very highly trained workforce, the population is so small that it would be difficult to quickly recruit multiple PhDs with an expertise in clotting. Here, in just six weeks, we recruited the first 21 people, 14 of whom are PhD level researchers. In fact, we had 300 applications. It just verified that it would just be a huge advantage for us in terms recruiting the kind of people we needed."
With a staff size currently at 27, expansion is already underway and the staff will eventually number about 65. Until now, most research and development has been performed in Denmark. This is true both for diabetes and bio-pharmaceutical research that involves growth hormone, female hormone replacement, and haemostatic agents. The primary product is NovoSeven (coagulation factor VIIa), used for the safe and effective treatment of bleeding episodes in people with hemophilia.
Factor VII/VIIa is a naturally occurring protein found in the blood and plays a crucial role in the coagulation process. Typically, hemophilia is treated by the use of recombinant protein products, such as recombinant factor VIII. But, unfortunately, some patients develop an antibody against the protein given to them. "When that happens, and a doctor gives them the VIII, it just gets bound to an antibody and it doesn’t work," says Carr. "If that happens it dramatically complicates the care of the patient. By taking the medicine, the patient is actually worse off."
NovoSeven was the discovery of a Swedish doctor, Ul#la Hedner, who believed that a different clotting factor that didn’t require VIII or IX could activate the system. Along with some colleagues, Hedner isolated enough of the molecule, VIIa, to successfully treat several patients. Clinical trials began for hemophilia in the late 1980s. By the mid-1990s it was available in Europe, and by the late 1990s it was available in the United States and approved by the FDA for the treatment of hemophiliacs who develop inhibitors.
"NovoSeven helps people who are dramatically bleeding with hemophilia to stop bleeding," explains Carr. "This is true even if they have developed an inhibitor (an antibody that makes the normal treatments not work well). It’s a pretty tough situation to handle clinically and this drug is made for that purpose."
With NovoSeven’s track record of success, researchers at the North Brunswick facility will explore new methods to prevent or stop critical bleeding, including treatments for trauma, stroke, and intracranial hemorrhaging (ICH). "We are having trials with people who don’t have hemophilia but are having bleeding into their head," says Carr. "It is worse than a thrombotic stroke in that the outcomes are much worse and the mortality is much higher. Unfortunately, two-thirds of the patients who do survive will be damaged so severely that they will not have a truly functioning lifestyle."
Up until three years ago, there was no effective treatment for ICH with physicians basically watching to see what happens to the patient. "If you have other patients who are bleeding and you’ve tried everything else, people will often try whatever they can get their hands on," says Carr. "A pathologist told me once, `All bleeding stops, your role is to make it stop before the patient dies.’" Some neurologists postulated that NovoSeven might be effective in containing intracranial bleeding. "It was thought that when the patient comes through the door, maybe there is still some ongoing bleeding and that if we can stop that bleeding maybe we can have a better outcome," explains Carr.
After some initial success, this eventually led to a phase II trial of NovoSeven in ICH patients. After receiving a fairly positive outcome a Phase III worldwide trial was initiated, currently ongoing. "It should finish by the end of the year," says Carr. "This will hopefully provide evidence that will allow for approval of NovoSeven in the treatment of ICH. This is exciting because maybe now we have a way of treating what was previously untreatable."
Carr learned to accept reality at an early age. Born and raised in Greensboro, North Carolina, his mother was a part-timer schoolteacher and his father worked in the cotton mill making blue denim. "He was the hardest working man I ever met," says Carr. "He had two and a half jobs and would work two shifts everyday, leaving home at 6:30 in the evening and coming back the next day around noon. He did that six days a week. But you know, when you work for minimum wage and you have five children, you do what you have to do."
Carr’s four sisters, including his twin, are all married with children and still living in Greensboro. "People don’t move around as much in the south," he says. "I also have a lot of relatives in the coastal plains of North Carolina."
Carr majored in physics at Davidson College in North Carolina, despite the fact that it was not his first love. "I wanted to be an astronaut, but got too big," he says. "In the old days astronauts couldn’t be more than five-feet-eight. So I went into physics." While serving in the signal corps of the Army Reserves, Carr also went to graduate school, earning his PhD in biochemical engineering from the University of North Carolina.
"In biochemical engineering you can do almost anything," he says. "But I quickly realized that at that time, in the 1970s, if you went into biochemical engineering you would either be a physician and work for yourself or you would work for a physician. That much was clear to me."
So he decided to go to medical school at the University of North Carolina. "Of course, in Chapel Hill, that is the home of Kenneth Brinkhaus [the man who first described hemophilia in dogs and subsequently did pioneering work in blood coagulation and hemophilia thereby keeping hemophiliac dogs healthy]," says Carr. "He came up with the first real treatments for hemophilia. So it is a clotting place. I got in with that group in my training, and I stayed there."
After finishing medical school, he did a residency and fellowship at UNC and stayed there for the 14 years. Then he went to the Medical College of Virginia in Richmond, where he was an associate professor and ran the hemophilia center. "We had over 200 hemophiliacs there and I had been working on research in coagulations in the 1970s when I was at the University of North Carolina," says Carr. "So I know the clotting community, which is not that big, amazingly enough. People know each other fairly well."
Carr is married and has four children: a daughter who is a junior at Virginia Tech, another daughter in high school, and two school-aged sons. His wife, originally from Virginia Beach, supports Carr’s second career, as an officer in the Army Reserves; her father was a naval aviator.
Having served as a physician in the reserves for nearly three decades (he has the rank of colonel), it is obvious that the military has played an important role in his life. "I have always liked soldiers," says Carr. "With multiple activations over the years, it is something that is very different from the rest of my life. When I am deployed, I work as a physician so I use all kinds of ways to stop the bleeding of wounded soldiers."
Serving in the ROTC program during his first two years at Davidson College in the late 1960s Carr elected to continue on for practical reasons. "This was in 1967 and `68 and in my mind I knew I probably was going to go to Vietnam and I’d rather be an officer than an enlisted man at that point," he says. But the climate of the war changed, and by 1971 the army had more second lieutenants than it needed, so Carr was put into the reserves, and he stayed until his time was up in 1979.
While working at the University of North Carolina, Carr spent many hours moonlighting in emergency rooms. "I was actually board eligible in emergency medicine because I had worked 7,000 hours in an emergency room. It was difficult, but I made a lot of money." But when he took the job at the Medical College of Virginia, he quickly realized that he made more money as a resident and moonlighting than as a university faculty member.
"We needed the money, so I went to my boss and said I wanted to moonlight," says Carr. "He said no, only residents and fellows were allowed to moonlight. So I made an army recruiter’s day by walking into the recruiting station and saying I’d like to sign up for the reserves. He almost fell out of his chair when I told him that I was a physician because recruiters get points for recruiting people. You get something like a gazillion points for bringing in a physician."
Now back in the army reserves, the first thing Carr realized was the dramatic change in the mood of his fellow reservists. "The reserves were now a very positive group of people who enjoyed what they were doing and thought it was important," he says. After serving in Iraq for six months during Operation Desert Storm, Carr realized that he wasn’t that far from getting his 20-Year Letter, so he decided to remain for awhile longer.
"The army sends me places that I would never otherwise go, he says." "How many physicians in New Jersey have seen leprosy? I saw that in Paraguay. I was in the desert of the Dominican Republic. Most people don’t realize that there is a desert there, but the army found it and sent me there."
It was while on one of his military activations from the Medical College of Virginia that Carr first considered the possibility of leaving academe to work in the pharmaceutical industry. "I got back from Fort Hood and discovered that my office had been flooded because a pipe had burst three floors up," he says. "I then got a call from a friend who worked for Novo Nordisk, and she said that sometimes when you have a flood like that it is a sign that maybe you ought to consider doing something else. I thought, maybe I would."
Soon afterwards Carr was activated and sent to the Dominican Republic. Shortly after returning he received word that he was going to be sent to Kosovo for six months. "In the middle of that I got a call from Novo Nordisk asking whether I would consider working for them," says Carr. "I told them that I would, but that I was going to be activated in three weeks. But I came up for a brief visit and it was very positive." When he returned from overseas, Carr was hired as Novo Nordisk’s executive director of clinical research. That was in March of last year. Six months later he had the title of vice president of research.
The North Brunswick facility will focus on basic research, ideas brought by academics who have an interest in hemostasis or blood clotting, as well as those from small biotech companies that might like to partner with a larger company for evaluation and development.
According to Carr, the gene for hemophilia is fairly common, while the full expression of it is not that common. "There is a big spectrum of disease presentation depending on how much factor VIII you have," says Carr. While normal factor VIII is 100 percent, if you have just five percent then you likely have mild hemophilia. This means that you will bleed excessively if cut or hurt, but spontaneous bleeding is unusual. If you go anywhere from five to one percent, then you have what is called moderate hemophilia. Some of those patients will bleed spontaneously, bleed into the joints.
But young people now have an excellent chance of living a long life, according to Edwin Wilson, a 64-year-old hemophiliac who lives in Greensboro, North Carolina, and heads a state association for hemophiliacs. Asked whether he and his cohorts are pessimistic complainers or cheerful optimists, he chooses the latter. "The positive outlook is the better outlook, because complaining gets you nowhere," says Wilson.
As with most treatments, coming up with an effective therapy for clotting disorders has been something of a roller coaster ride. The traditional remedy was to give the clotting factor back to the patient. For years this was done by giving plasma, but it is very difficult to give enough plasma and there is always the risk of reactions from the blood transfusion and problems with viruses.
So in the 1960s, concentrates were made and it had a dramatic impact on the treatment of hemophilia. "We could give people the factor VIII concentrate or the factor IX concentrate and stop their bleeding," explains Carr. "Eventually we realized, in the mid-1970s, that if we could give them a little bit every day, then they simply wouldn’t bleed. It absolutely changed their lives so that now they didn’t get this crippling joint disease and suddenly people got out of wheelchairs and were walking around, they started playing tennis. It was just an incredible time."
But unfortunately, doctors and researchers didn’t realize the vast number of viruses that were getting into the products. "It took a thousand donors to make one vial of concentrate," says Carr. "Since viruses are fairly ubiquitous, those were virtually all contaminated with hepatitis B and C. Then in the early 1980s they began to be contaminated with HIV. This had a devastating impact on the hemophilia population. Eventually this led to a new emphasis on the development of recombinant protein products, made by yeast or other forms, that are not taken from other people. This effectively removed the risk of viral contamination. These became clinically available in the mid-1980s and have since gone through several generations of recombinant products."
For hemophilia patients, the major threat of possible exposure to viruses is ongoing, the worst being HIV and hepatitis C. "We’ve done amazingly well over the years with HIV in the hemophilia population," says Carr. "Did we lose a bunch of hemophilia patients? Absolutely, but we now have patients with hemophilia who have been HIV for 20 years." This success can be attributed to what is called the HEART therapy (highly effective anti-retroviral theory). "We have done amazingly well keeping those patients going," says Carr. "They are very in tune with their disease because they have to be."
The other bad virus, hepatitis C, has proven more difficult to treat. "When you get hepatitis C, which is almost always from a blood transfusion, you typically don’t get rid of the virus," says Carr. "It’s not like hepatitis A or B, where you tend to get rid of the virus. With hepatitis C, you tend to harbor it and less than 10 percent will get rid of the virus and the other 90 percent will continue to have it."
Carr says that in a third of those patients, it will never cause a problem. Another third of these patients will have intermittent laboratory abnormalities. It remains in the liver, causing what is called chronic active hepatitis, but it doesn’t cause any other problems. The other third get cirrhosis. "For a long time we had therapies that didn’t help much," says Carr. "But most recently we have gotten much better at treating hepatitis C. But it just seems so unfair that you have a population that had inherited, through no fault of their own, a bad disease. Then you treated them and you gave them another bad diseases. It was just like Job. But we are doing much better now."
As a resident of New Jersey, for the first time in his life Carr is a not calling the south his home. Officially, Carr is still a member of his Richmond unit and continues to occasionally slip down to Virginia help out with drills. "Since I’ve been up here I’ve looked around for a unit maybe at Willow Grove or maybe Fort Dix. But since I’m getting near the end – I hope – I just kind of stayed with the unit that I’ve been in," he says. "I was commander of that unit a couple of times, so I know them very well. I’ve got my 20-Year Letter, which is enough to let you retire, but right now there are not a whole lot of people in the medical side of the military being retired. Until the situation improves a little bit I think that will be the case."
For Carr, keeping things in perspective is something that serving in the military has continued to instill in him. "Some of the things that you go through make you understand things about living," he says. "A warm shower is a wonderful thing. The army has a way of reducing your expectations to the point that getting a hot meal is a great thing. I got one this week. Wow! Getting a clean uniform or just being clean, after awhile these basic things become something that makes you very happy."
He also continues to enjoy the work he and his colleagues at Novo Nordisk are doing to improve the lives of hemophiliacs. "When I was younger I just knew that I would never want to go into oncology because I don’t want my patients to die," he says. "I’m not saying that we don’t need oncologists, we absolutely do, and I admire them greatly because that is something I could not do. I’d much rather be able to stop the bleeding and have my patient live."
"So, I have to tell you, I used to have to go to oncology clinics because it was a part of my training. But I found that I might go down there and find myself grumbling because my paper didn’t get accepted or my grant didn’t get funded or the experiment didn’t work. But when I came out, I’d be this person who knew he didn’t have any problems. The people at the oncology clinic have problems and they deal with them amazingly well. I always felt like I took more away from that clinic that I took to it. That is true for a lot of things in my life. I have these resetting moments that let me know how good I have it."
Novo Nordisk Research U.S. (NVO), 685 Route 1 South, Technology Center of New Jersey, Building 4, North Brunswick 08902; 732-214-1550; fax, 732-214-2499. Marcus Carr MD PhD, vice president research US. 
Novo Nordisk Inc. (NVO), 100 College Road West,Princeton 08540-6213; 609-987-5800; fax, 609-987-5394. Martin Soeters, president. 