Firm poised for cancer breakthrough
By Steve Wartenberg
Staff Writer
A doctor pursuing an academic career and a businessman suffering from a rare form of the disease teamed up to develop a potential cure.
HORSHAM —It didn't seem like a life-altering day, one that would forever change Dr. Rifat Pamukcu's career and lead to a possible treatment for a rare form of colon cancer.
It was 1987 and Pamukcu was a fellow in the University of Chicago's department of gastroenterology.
He had no idea he was about to become a cancer crusader.
"I was working in the lab, wearing jeans and a sweatshirt," he said. "I get a call, to come see a patient."
He threw on a lab coat and walked into the patient's room.
The patient, Floyd Nichols —suffering from familial adenomatous polyposis, a disease characterized by the growth of pre-cancerous polyps on the inner lining of the intestines, that left untreated develops into colon cancer —took one look at Pamukcu, laughed and asked: "You're a doctor?"
This was the start of a great friendship, one that would eventually lead to the creation of Cell Pathways Inc., a Horsham-based pharmaceutical company. After years of research —led by Nichols, the fund-raiser and eternal optimist, and Pamukcu, the scientist —the company seems poised for a breakthrough: On Oct. 25, the Federal Drug Administration accepted the company's new drug application for Aptosyn (or exisulind), which in tests has eliminated the precancerous polyps associated with FAP.
This is the first hurdle in the long process of getting the drug approved for widespread use.
Tests have also suggested Aptosyn is effective in fighting several other forms of cancer.
"For (FAP) it's a small, but very needy and significant market," said Cell Pathways president Robert Towarnicki. "It's these other (cancers) where the major market opportunity lies."
Unfortunately, Nichols didn't live to see his dream come true.
Although his FAP was under control, he died in 1996 from another, unrelated form of cancer in the lining of his stomach.
"It was just unbelievably bad luck," Pamukcu said, adding that losing Nichols was like losing his own brother.
They were a team, and now Pamukcu was on his own.
"When I got depressed about the setbacks, he encouraged me," Pamukcu said. "When he got depressed about raising money, I encouraged him."
Fortunately, Nichols may have helped find the cure for FAP in time for his son, Eric, 11, who has inherited the disease from his father.
The Nichols story
From the start, Pamukcu recognized and was drawn to Nichols' indomitable spirit and his "refusal to take no for an answer."
When he was 19, Nichols was diagnosed with FAP.
Because many people don't know they have the disease until it becomes cancerous, it is hard to say for sure the number of people it affects.
Estimates are 25,000 in this country.
"Back then (in the early 1970s), the colon had to go," Pamukcu explained. "The end of the small bowel was brought out through the abdomen and the patient had to live with a bag."
Since then, the operation has advanced: The colon is removed and the small intestine is connected to the rectum. It's still an invasive, life-altering operation.
Getting a bag wasn't acceptable to Nichols, who searched the country for an alternative procedure and finally found one at the Mayo Clinic, where doctors created a pouch out of his small intestine.
He was one of a small test group who underwent the experimental procedure.
"The waste collects inside the pouch and he could drain it himself a few times a day —there was a sort of plug on the outside," Pamukcu said.
Fast forward to 1987 and Nichols is 35, married and has created and sold his successful computer company. He began to notice blood coming out of his pouch.
Tests revealed hundreds of precancerous polyps.
"They were so advanced they could have become cancerous in a year to five years," Pamukcu said.
Doctors wanted to remove the pouch and fit Nichols with a bag. He couldn't stand the thought, and once again began searching the country for an alternative.
Finally, he talked to a doctor who had heard a lecture in which another doctor discussed FAP patients who were treated with sulindac, an arthritis drug. It made the polyps mysteriously disappear.
"Floyd told me about it and I got all the research," Pamukcu said. "The attending physician said no, it was too experimental and Floyd got ticked off. He basically told the attending physician off and I was standing there, with my career flashing before my eyes."
Eventually, a different attending physician was put in charge of the case; he allowed Pamukcu to treat Nichols with sulindac.
"Within three months his polyps were gone," Pamukcu said. "It was the most remarkable thing I'd ever seen."
A New Discovery
With financial support from Nichols, Pamukcu began doing research, which led him to believe it wasn't the anti-inflammatory drug sulindac that was killing the polyps.
"When it is taken, it is converted by the liver into two compounds, " Pamukcu said.
The first is an anti-arthritis metabolite that produces all sorts of side effects in the kidneys and gastric system, including ulcers.
Nichols did in fact suffer from ulcers.
Pamukcu became convinced the second metabolite, previously believed to be inactive, was also destroying the polyps.
"If it was, this was good news because, if we could isolate it, it wouldn't have all the side effects of sulindac," he said.
Over the next several years, this is what they did.
Nichols chipped in his own money and they formed FGN Inc. —his initials.
"Anyone can have vision," Pamukcu said. "But if you don't have the entrepreneurial skills, if you don't have money, you can't do great science."
This was Nichols' job, and he was a tireless fund-raiser.
The initial tests —on animals —went well.
"We found that the second metabolite didn't have all the gastric side effects and was killing every cancer we threw at it," Pamukcu said. "We felt as if we had a tiger by the tail."
Still, they were a long way from a cure, and Pamukcu and Nichols went through a series of ups and downs. By 1993, they were ready to test their metabolite on people with FAP.
As Pat Weidner knows all too well, FAP is a genetic disorder.
This Ohio woman inherited it from her father and has passed it on to her two children. All three had to have most of their colons removed and their small intestines connected to their rectums.
Weidner was part of the clinical trials and calls Cell Pathway's new drug Aptosyn "a miracle."
"I had all these polyps, maybe 20 to 30, and my doctors were starting to consider what to do," she said.
Surgery to "burn off" some of the polyps was an option, but not one Weidner was looking forward to.
"That can perforate your colon," she said. "That happened to me in 1991, and I almost died."
An equally unappealing option would have been to remove the remainder of her colon.
In 1993, she began taking Aptosyn.
"My polyps are almost all gone," she said. "And the longer I'm on it, the less I have."
She reports absolutely no side effects.
While this is great news for Weidner, it's even better news for her children —and their future children. If and when the gene is detected, they can begin taking Aptosyn and may never develop the deadly polyps.
While the tests went well, Pamukcu began to notice Nichols wasn't looking well. After several trips to an array of doctors (Pamukcu was no longer his physician), it was discovered he had a tumor in his liver and cancer in the lining of his stomach.
Cell Pathways moves on
When Nichols died, Pamukcu was devastated.
Before he died, Nichols was aware of the positive test results and that there was hope for his son, Eric, who has developed some polyps. He is currently part of an on-going clinical test for children.
While he'll probably have to take Aptosyn the rest of his life, he could avoid surgery.
There was never any question he would continue the work they had begun together. A search for a new chief executive officer brought Towarnicki to the company.
Tests continued, and the FDA is now evaluating Aptosyn.
In the mid-1990s, Pamukcu decided to move Cell Pathways to this area, first Conshocken and later Horsham.
"As time went on, we found we had more and more consultants in the Philly area," he said. "Plus, I have a son with a learning disability and there are a wealth of schools for that in this area."
"I'm not a magic-bullet kind of guy," Pamukcu said. "No one agent treats or cures every cancer. We're adding to what's already out there."
One of the benefits of Aptosyn, according to Pamukcu, is that it's "one of the first agents that can affect cancer without all that thermonuclear warfare on the body."
In other words, traditional chemotherapy cannot distinguish between cancerous and noncancerous cells and kills both.
Normal cells live a short period of time, while precancerous cells hang around, multiply and eventually become cancerous. Aptosyn, according to Pamukcu, blocks the enzyme that permits this and "allows them to die their normal death with no effect on normal, healthy cells, and therefore we wouldn't expect the side effects associated with conventional chemotherapy."
"This is very promising," said Dr. Randall Burt, chief of gastroenterology at the University of Utah. "It only seems to affect the abnormal cells and causes the cell death (of the precancerous cells) to return to normal. This is the key since cancer is basically cells that grow too fast and die too slow."
Burt was the one who first told Nichols about sulindac and has been following Cell Pathways progress closely.
"(Pamukcu) is a brilliant scientist and businessman," Burt said. "I credit him with much of the success. And now he has Bob Towarnicki, who has all the business smarts, and they're a team I have a lot of admiration for."
Accolades and professional recognition are one thing.
People like Pat Weidner are another.
"We try not to lose sight of the human component," Pamukcu said. "It's easy to distance yourself from that, as you get bigger and busier, but part of our corporate culture is to maintain it."
Several years ago, Pamukcu had to decide what to do with his career: continue along the academic route or work full time trying to find a treatment for FAP.
"I was discussing it with my wife, and one of the questions she asked me was, 'When you're 60 and look back on this decision, what will you say if you didn't do it?'
"I said, 'I'll kick myself.'"
Sunday, October 31, 1999
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