When Scott Phelps visits his mother, she calls him Bobby. Pauline Phelps gives her son a hug, sits on the couch next to him and forgets he’s there. The 84-year-old prefers to talk to her brother, Paul, or Aunt Shorty, both of whom died decades ago.
"We’re ready to go home," Pauline says to the air in front of her. "We are home," Scott, 52, of Ahwatukee Foothills tells her.
Not really. Pauline, who is cared for in an Ahwatukee Foothills group home, lost the life she once knew and the mind she once had after participating in a clinical drug trial for Alzheimer’s disease.
The drug being studied, AN-1792, held the promise of becoming a vaccine that could prevent or slow the decline of Alzheimer’s — a disease that afflicts an estimated 4 million people nationwide, including 85,000 in Arizona, yet has few effective treatment options. Instead, the experimental drug made about a half dozen people like Pauline worse.
"It had really strong and robust science to support it," said Dr. Marwan Sabbagh, director of clinical research at Sun Health Research Institute in Sun City. "Just a few years ago, we thought we were on the verge of curing Alzheimer’s."
Today, Pauline’s experience with AN-1792 represents how far Alzheimer’s research has come, and how far it still has to go. Her tragedy grows from the desperation that drives families of Alzheimer’s victims to heavily marketed drug trials, and the risks inherent in the drug trial process.
"She’s not the mother I grew up with," Scott said. "If I had to do it all over again, obviously we would have never done that (drug trial). I lost the very thing I was trying to hang onto."
After her husband’s death, Pauline lived alone in a Mesa retirement community. She loved bingo and shopping, and called Scott, her only child, every day at 6 p.m.
But signs of memory loss were emerging. Pauline started repeating questions. A missing wallet was found in the laundry hamper. And she lost her way driving home from church one day.
Then Scott, an assistant to Phoenix Mayor Phil Gordon, saw a newspaper story and an advertisement for a clinical drug trial that offered hope to people with memory problems. Researchers were looking for participants with mild to moderate Alzheimer’s.
The timing seemed perfect. Just when his mother started showing signs of dementia, a promising drug was on the horizon.
The consent form from Pivotal Research Centers, signed by Pauline in October 2001, stated that all the possible side effects of AN-1792 were not fully known. But in animals, the most common symptom was mild skin irritation at the injection site, one of 14 possible side effects listed.
On Oct. 31, 2001, Pauline received her first of a series of AN-1792 injections. Worldwide, about 375 people were getting the shots, with one in five receiving a placebo. Scott hoped his mother was getting the real drug.
On Nov. 28, 2001, Pauline had her second injection, with doctors checking her arm for any irritation.
Then on Jan. 17, 2002, several days before she was due for her third injection, a woman playing bingo near Pauline noticed she wasn’t covering the squares on her cards as numbers were called. The next night, with the sound of the television coming out of her open door, Pauline was found lying naked on her couch with her mouth wide open.
"She looked like she was dying," Scott said.
CLINICAL TRIAL COLLAPSES
When Scott called to cancel his mother’s appointment for her third shot because she wasn’t feeling well, Pivotal Research officials insisted that he bring her in, he said. Other participants had become ill from the drug, he was told, and Pauline needed to be evaluated.
Scott’s mother was not getting the placebo. She was one of 18 people in the trial who developed encephalitis, swelling of the brain, and one of six who never recovered, according to a follow-up study on trial participants.
"Literally overnight, she went from being a relatively normal functioning human being to being able to do literally nothing else," Scott said.
Asked why encephalitis was not among the side effects specifically listed in Pauline’s original consent form, Dr. Louis Kirby, founder and medical director of Pivotal Research, said he could not answer because of a lawsuit filed by Scott and Pauline Phelps against Pivotal and the maker of AN-1792, Elan Pharmaceuticals.
Pivotal had Pauline sign a second consent form June 12, 2002, to continue in a follow-up study of trial participants. This form stated that about 5 percent of participants developed symptoms associated with encephalitis.
Scott is suing the companies for failing to originally disclose the risk of encephalitis, and for failing in its agreement to pay for AN-1792-related medical expenses not covered by Pauline’s health insurance, according to the lawsuit.
Sarah Datz, an Elan spokeswoman, said company officials could not comment for this story except to say they deny the allegations.
On Jan. 17, 2002, the research alliance of Elan and American Home Products announced they had suspended injections of their experimental drug, AN-1792, worldwide. On March 1, 2002, the companies halted the clinical trial permanently.
CAUGHT OFF GUARD
Some Alzheimer’s researchers said they never expected brain swelling from AN-1792. Mouse studies did not show encephalitis. In fact, the results were so groundbreaking, they were widely publicized in scientific journals and the media.
Researchers were looking for a way to prevent or clear out protein deposits in the brains of Alzheimer’s patients. The deposits, or plaque, are associated with the disease.
By injecting AN-1792, a synthetic version of the protein, researchers hoped to stimulate an immune response that would destroy the brain plaque. The strategy worked in mice genetically altered to produce the human protein.
The Food and Drug Administration approved human clinical trials of the drug, and AN-1792 passed its Phase 1 trial for safety in about 100 people. But Phase II, which tested the drug’s effectiveness, ran into trouble.
Instead of stimulating the immune system to attack only the plaque, AN-1792 stimulated an attack on the brain itself, causing inflammation in some participants. "It was a bolt from the blue," Kirby said.
Researchers suspect that problems didn’t crop up in animal studies because mice have a limited immune system.
The failure of AN-1792 set Alzheimer’s research back significantly, forcing scientists to rethink ways to fight the disease, Sabbagh said.
"When you have a study like AN-1792, it makes people gun-shy to try progressive therapies to treat Alzheimer’s," he said. "It was clearly a setback because it had a chilling effect on immunological therapies."
But the setback also was a step forward, researchers said. Autopsies of participants who have died since the trial showed that despite the immune system’s attack on the brain, plaque was removed.
"Even with an adverse effect, it pushed science forward," Sabbagh said. "There is a downside because people suffered, but the upside is the next generation (of drugs) will be better."
New drug trials for Alzheimer’s disease are under way at Pivotal Research. But this time, researchers are injecting antibodies to the plaque, hoping to avoid the kind of immune system reaction sparked by AN-1792.
"Without doing clinical trials, (Alzheimer’s) will continue to be a devastating illness," Kirby said. "Without people volunteering for clinical trials, the developments will come much slower."
A LIFE LOST
For Scott and Pauline Phelps, the price of scientific progress was too great.
There are signs of the woman Pauline once was — such as the flashes of recognition when her son walks in the door — but they are gone in an instant.
Instead of gradually declining to Alzheimer’s over many years, Pauline’s mental state plummeted after her participation in the AN-1792 trial.
Today, large, unexplained blisters cover the palms of her hands. Days are spent sitting on the couch in the family room, burping between words to people others cannot see. She never picks up the phone. She remembers nothing about her 45-year marriage.
Scott continues to visit her every other day, but he has stopped testing her memory with questions.
There is not much memory left to test, he said.
"Some days I’m kind of numb to it. Other days, I have walked away from this place with tears in my eyes," he said. "Nothing good will come of this for her. I do hope something good comes of it for others."