Dr. Tony Wood, a young chemist looking for his first job after completing a post doctorate, agreed to replace a retiring scientist as head of a Pfizer antiviral chemical group. On his first day in the new role Wood met with his predecessor. “I remember sitting in his office feeling like my career is already finished as he tells me virals are a tough area and that I’d never discover a medicine. I remember thinking at the time, ‘This is not going to be the case; I’m determined to find a medicine here.’”
“I feel incredibly privileged to be part of the team, to be in the right place at the right time to convert science into something of value to mankind.”
—Dr. Tony Wood
In fact, the odds were against Dr. Wood. Scientists during an entire career are much more likely to discover many times what doesn’t work than they are to find a medicine that meets the FDA’s standards for safety and efficacy. But Dr. Wood had become part of a team that beat those phenomenal odds. The team repeatedly overcame obstacles, discouragement and setbacks. Sleepless nights often followed nail-biting days. In short, the process worked like this, says Dr. Wood: “We’d solve a problem, identify a new one, solve a problem, identify a new one.”
Dr. Manos Perros was also new to commercial pharmac eutical research when he joined Pfizer in 1996. An accomplished classical pianist, Dr. Perros earned his Ph.D . in biochemistry in 1994 then worked as a researcher for two years at Yale University, a government-sponsored cancer research center in Heidelberg and at the Institut Pasteur, a Paris-based research foundation. “Very few discoveries in academia turn into drugs, and I wanted to go to a place drugs are discovered,” says Perros. “I was inspired to join Pfizer by both the medical need and the opportunity CCR5 offered.
“When I joined Pfizer the AIDS death trend was declining and people were saying, ‘HIV is solved; don’t worry about it.’ But being a biologist made it quite easy to see that there was only a short reprieve and the virus was developing resistance. It was very clear in my mind that new lines of treatment were required.”
Dr. Elna van der Ryst, meanwhile, was early in her career as a medical doctor in South Africa when the AIDS epidemic hit her native land with full force. “Every single South African has been touched by HIV, and even as a young doctor I lost friends and patients to the disease. Seeing patients die early in the epidemic shaped my career. For me, it was personal.”
Convinced there must be better options for treating the disease, she completed a postgraduate degree in virology and started to do research on HIV. After earning various degrees, including a Ph.D. with studies on HIV vaccines, she joined Drs. Wood and Perros at the Pfizer lab in 1999.
Rationally, the team knew at the outset that the odds of producing a medicine were
very, very low—much less than one in a thousand, says Dr. Perros. But in his heart, he believed. “You have to believe or you’ll never succeed,” he says. “You have to believe because there are many people who won’t. Some have the job of critiquing the work to make sure resources are being spent wisely, so project leaders have to be firm believers, standing behind the project. We must be champions of the work.”
Discoveries, Hurdles, Roadblocks
The Pfizer team began with critical knowledge: It had long been known that HIV infects T cells by binding to a cell’s surface via a receptor called CD4. Scientists also suspected that a second “co-receptor” was involved. But despite more than a decade of intense research, the elusive co-receptor remained a mystery.
Finally, in 1996, researchers in labs in New York City, Boston and Bethesda, Md., almost simultaneously discovered that for HIV to bind with the CD4 receptor, it must also latch on to one of two co-receptors, either the protein CCR5 or the protein CXCR4.
The idea that it might be possible to target a receptor instead of the virus was intriguing, but Dr. Wood says he felt almost schizophrenic as he pondered the potential. “At one level you look and say (CCR5) is a great protein receptor. But at another level it’s a class of receptor that is a notoriously difficult target. We did the screening project with great anxiety, but we were delighted with the first experiments.”
But not for long.
“We were all very committed to wanting to make a difference in the lives of HIV patients.”
—Dr. Tony Wood
For nine months, the team kept finding compounds that were very effective in blocking the receptor but that didn’t hinder the virus. “At that point we were probably a quarter of the way from giving up and stopping all work,” says Dr. Perros.“For nine months we had many sleepless nights.”
Finally, a big moment: The team found a small molecule with an antiviral effect. “We were very excited and I thought, “Wow, this will go quickly now and we’re going to find a fantastic development candidate in no time at all,” says Dr. Wood. “We were working on increasing the potency of the first compound, but then another story started to emerge.”
Scientists were just learning about an ion channel in the heart that many basic compounds can bind to and potentially cause a cardiac toxicity that can lead to death.
“We tested our potent compounds and were absolutely crestfallen,” says Dr. Wood. “They were even more potent binders to the channel than they were binders to CCR5.”
The team now had to find new compounds that had the earlier positive results of being antiviral and binding to CCR5, but that did not bind to the heart channel.
The overall timetable was surprising to Dr. Perros. Early on, when something went well, it seemed as if the drug was within reach. “I was coming straight from an academic lab and so had no experience with what needed to happen,” he says.
Eventually, though, a promising candidate emerged: A compound good enough to test in preclinical trials.
Once a clinical candidate is nominated, most of the team working on the discovery phase stands down. But everyone kept a close watch on what was happening, says Dr. Wood.
“The drug was almost like our children for us,” he says.
“Both as a scientist and as a physician, working on SELZENTRY was the most exciting time of my life.”
—Dr. Elna van der Ryst
Dr. van der Ryst, who designed the early human studies and helped determine appropriate doses, remained intimately involved throughout the development process. Even when the results of clinical trials looked positive, however, Dr. van der Ryst did not take time out to celebrate.
“The feelings were quite strange because at the same time we might have been tempted to just celebrate the results, we were looking for problems. The development program continued and the potential for setbacks was always there, so there was no moment to just stand back and say, ‘Look, how fantastic!’ ”
As the clinical trial investigators did their work, Dr. Wood received anecdotal information in emails. “There were anecdotes about patients who were preparing to die but they were put on SELZENTRY and it transformed them and they were returning to their lives. That kept me going. It’s still what gets me out of bed in the morning when things are not going well.”
He also got the opportunity to meet patients. He remembers in particular a San Francisco man who moved to Holland because he was able to enroll in a clinical trial there.
“Imagine moving across the world, especially while you are ill, in the hope of finding a therapy,” says Dr. Wood. “He had been on an intensive antiviral regimen that was so toxic and had such side effects he couldn’t function. He described being put on SELZENTRY, his viral load went down, and there he was, happy and talking about how he’d be able to live life again.”
Dr. Perros too was able to meet patients. “Many had run out of options and SELZENTRY was a lifeline,” he says. “It doesn’t take tens of thousands or millions of patients to make the work feel worthwhile. Every single life is important.
“To sit with one person who survived and is healthy brings a tremendous feeling of satisfaction.”
More than a decade of work came to fruition with FDA approval of SELZENTRY in 2007.
“It doesn't take thousands or millions of patients to make the work feel worthwhile. To sit with one person who survived and is healthy because of medicine you worked on brings a tremendous feeling of satisfaction.”
—Dr. Manos Perros
SELZENTRY is indicated for use in the United States for patients with only R5-tropic HIV-1. It is not without side effects—it carries a boxed warning relating to hepatoxicity—but it has proven to be a useful medicine for patients with R5-tropic HIV.While initially approved for experienced patients, it has since been approved for new patients in the U.S.
But the work goes on.
Researchers are currently working to determine if the drug is safe and effective for children. It’s also being tested in HIV patients co-infected with hepatitis C. A large, long-term safety study is underway.
The scientists, clinicians and managers whose roles in SELZENTRY are done are working on new medicines. But even now, Dr. Wood and all those who worked on SELZENTRY can know that when they retire, they can look back and say, “Yes, the gifts I’ve been given, I’ve used in a good way.”