Alzheimer's clinical trials provide sliver of hope to 'heroic' volunteers

View full sizeAngela Chillemi gives Rochelle McCloskey a hug. McCloskey, 75, of Freehold at her weekly hair appointment at 33 West Salon. McCloskey, who is in the early stages of Alzheimer's disease, is a participant in a clinical trial.

By Susan Todd and Amy Ellis Nutt/The Star-Ledger

A dreaded inevitability seeped into Rochelle McCloskey’s life in 1996. That was the year her mother died of Alzheimer’s. Two years later, her aunt did, too.

It was a rough stretch that got rougher when McCloskey was diagnosed with breast cancer in 2007 and endured three months of radiation. By 2009, the Freehold Township wife and mother was healthy again and cancer-free.

Occasionally, though, McCloskey’s mind seemed clouded. She lost her way on roads she had driven for years, directions confused her and she repeated herself.

"She was functional and capable, but something was amiss," her husband, Pete, said.

Today at 75 she is both a patient and a volunteer, one of thousands of men and women, nationwide, who have been diagnosed with Alzheimer’s and have chosen to sign up for a clinical trial as pharmaceutical companies race each other to discover a cure, or at least a way to slow the disease. This past week, the world of Alzheimer’s research was rocked by news that a drug awaited with great anticipation by doctors, patients and caregivers had failed in clinical trials. Even with the well running dry, however, McCloskey and thousands of others in clinical trials are holding fast.

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For these volunteers, a clinical trial can be alternately dangerous, monotonous and frustrating. Ultimately, these medicines are a gamble, a throw of the dice against the certainty of dementia and death. They aren’t simply the next best hope for Alzheimer’s patients. They are the only hope.

McCloskey talks of the trial as a treatment more than an experiment. It’s not clear if she understands she may not be getting the drug being studied because a computer randomly assigns some participants a placebo. The trial is also double-blind, which means neither she nor the doctor know who is receiving the trial drug. What she does seem to know is that the trial has repercussions.

"I think it’s very important thing," she said. "We do have a daughter."

"Volunteering is a heroic act," said William Thies, chief medical and scientific officer for the Alzheimer’s Association. "It doesn’t get portrayed that way very much, but it’s selfless."

IN NEED OF A WIN

It’s been nine years since the Food and Drug Administration approved a major treatment for Alzheimer’s. Of the five on the market, none attacks the disease, just the symptoms.

How much is riding on the race to find a "Holy Grail" medication?

A win "would be euphoria, crazy party time," Mark Schoenebaum, a health care analyst, told Bloomberg recently about one late-stage drug trial. "It could be the biggest upside surprise in the history of the pharmaceutical and biotech industry."

View full sizePaul Newman, a 56-year-old sufferer of early-onset Alzheimer's and his wife, 50-year-old Jill Newman pose for a portrait in their Red Bank apartment.

As illnesses go, Alzheimer’s is particularly wicked. There are two hallmarks to the disease’s double-fisted pathology: amyloid plaque and tau tangles. Plaque develops when the brain fails to clear out normal amyloid protein fragments and instead they accumulate and harden between nerve cells. Tangles occur inside those nerve cells when misshapen tau protein prevents the transmission of nutrients from one part of the neuron to the other.

Both processes are progressive and fatal, slowly erasing a patient’s memory, then the ability to carry out the simplest habits of daily living, such as bathing, dressing and eating. Over time, Alzheimer’s unleashes so much havoc, a patient is unable to swallow or even breathe.

A FLOATING FOG

Pete McCloskey has become an Azheimer’s expert by necessity, aided, in part, by the fact he spent his career working with drug companies and at one time was president of Berlichem, a chemical manufacturer in Wayne that creates pharmaceutical preparations.

Now, McCloskey accompanies his wife everywhere. He is her caregiver, chauffeur and crutch. When she forgets something, her face goes blank. It happened once when Rochelle was asked about her birthday.

"When is my birthday?" she repeated, laughing nervously.

"Your birthday is in August," her husband said, patiently.

View full sizeAngela Chillemi holds hands with Rochelle McCloskey after she did her hair. McCloskey, 75, of Freehold at her weekly hair appointment at 33 West Salon. McCloskey, who is in the early stages of Alzheimer's disease, is a participant in a clinical trial.

Rochelle doesn’t forget everything. Instead, she seems to move in and out of a thick, but fleeting fog. When in it, she cannot recall the day of the week or how to subtract. Pieces of information elude her. It’s as if the hard drive in her brain is temporarily on the fritz.

During a memory test at the six-month mark, Rochelle could not remember what she ate for dinner the night before or why she retired in 1999, but she did know the difference between a lie and a mistake.

"One is deliberate," she said. "One is an error."

A NEW HOPE

As gambles go, volunteering to take a drug still in development is a long shot. Human clinical trials are necessary, but they are also experiments. There is no guarantee the patient will get better by participating, and because most of the studies are double-blind and randomly controlled.

In New Jersey, where clinical trials are a cottage industry operating in the shadow of the pharmaceutical industry, there are close to three dozen studies testing possible treatments for the brain-destroying disease.

After being diagnosed two years ago, Rochelle McCloskey’s doctor prescribed Aricept, one of the standard medications that treats the disease indirectly, by trying to boost cognitive functioning in healthy brain cells. Aricept, however, seemed to have had little effect on McCloskey’s symptoms, so last year her neurologist suggested she try a new clinical trial with Joel Ross, founder of the Memory Enhancement Center. Now, Rochelle McCloskey’s best hope rests with a drug called crenezumab, manufactured by Genentech.

In May, the large San Francisco-based company announced crenezumab would be the centerpiece of the first clinical trial to test whether a drug can prevent Alzheimer’s in asymptomatic volunteers. Most of the trial’s subjects belong to a very large extended family of some 5,000 Colombians who share a genetic mutation that causes early-onset Alzheimer’s at about age 45. That trial, based in Medellin, Colombia, will start sometime next year.

Rochelle McCloskey’s Phase-II crenezumab trial began in April. In this study, researchers hope the drug will help slow or stop the progression of the disease in patients with mild to moderate Alzheimer’s.

Last week’s announcement that Pfizer and Johnson & Johnson were stopping their bapineuzumab trials because of disappointing results, sent a shudder of pessimism through the scientific, pharmaceutical and patient communities. Crenezumab is in the same class as bapineuzumab and four other immunotherapies that have failed in the past few years.

All are monoclonal antibodies, targeting the toxic amyloid plaque. Although they are laboratory-created, they act the same way the body’s own antibodies do, destroying foreign proteins. Crenezumab and bapineuzumab were designed to destroy amyloid plaque. Bapi’s clinical trials, however, failed to slow the progression of the disease.

To understand how interdependent the pharmaceutical, scientific and patient communities are, you only need to consider Rae Lyn Burke. Burke, a scientist at the Stanford Research Institute, is an expert in vaccine development and one of the key developers of bapi. Last year, she revealed she had early-onset Alzheimer’s and was taking part in one of the bapi clinical trials that has now ended.

A 'DEVASTATING' SETBACK

For Jill and Paul Newman, last week’s bapi announcement was "devastating." Paul, who is in his mid-50s, was diagnosed with early-onset Alzheimer’s on Aug. 19, 2009. Jill was only 47 at the time and the couple, who grew up in New Jersey, were living in Florida. They moved from Middletown in 1990 because of Paul’s business — designing and operating assisted-living facilities for Alzheimer’s patients.

View full sizeDr. Joel Ross speaks to the St. Thomas Seniors at the St. Thomas the Apostle Church in Old Bridge March 12. Ross tries an outreach-styled strategy of collecting eligible volunteers for the clinical trials he runs on proposed treatments for Alzheimer's disease.

In Florida, Paul had been enrolled in the bapi trial for 18 months when Jill decided she needed more help and the couple moved back to New Jersey to be closer to family. Ross, the geriatrician, agreed to monitor Paul as he entered Phase III of the bapi trial, at which time they were informed he was indeed receiving the drug, not a placebo.

"We didn’t see any difference," Jill said about the bapi. "With early-onset, you decline so much faster."

Jill has not yet told her husband about the end of the bapi trial.

"Paul in his own mind thought he was cured," she said.

Today she must remind him to use soap when he showers and how to dry himself. She helps him dress in the morning, then gives him coffee and sweets because "that’s what he craves … It’s the same thing over and over every day."

Although she knew bapi wasn’t helping her husband, the announcement that the trial was being discontinued still hit hard.

"There’s nothing else out there," she said. "Absolutely no hope. Where do you go now?"

A CAREGIVER'S BURDEN

Pete McCloskey claims not to be discouraged by bapi’s failure. White-haired and broad-shouldered, he is a pragmatist.

"I’m sorry to see it happen, but that’s the nature of this game," he said. "Clearly the fact that another monoclonal antibody did fail is a potential setback, but bapineuzumab is not crenezumab. … I’m not overly concerned."

When work on crenezumab began in 2006, Genentech engineered the drug so it could be given in higher doses than bapi, which caused a dangerous buildup of fluid in the brain as dosages increased.

View full sizeDr. Joel Ross talks about the research studies on Alzheimer's ongoing at the Memory Enhancement Center in Eatontown. Rochelle McCloskey is enrolled in a Genentech drug study for Alzheimer's patients at the Memory Enhancement Center in Eatontown.

In a suburban neighborhood in Freehold Township, Rochelle McCloskey raised two children with her husband. She taught piano lessons. She sang in her church choir.

When her children grew up, she started working full time at Bristol-Myers Squibb to help earn money to pay for their college educations. At the pharmaceutical company, she moved up quickly, becoming an executive secretary to the president of the chemical division.

When she was 63, Rochelle retired from Bristol-Myers and spent her weekdays in New York City baby-sitting her granddaughter. That arrangement ended with Rochelle’s diagnosis. Since 2010, the fabric of her life has frayed and the map of her world has shrunk.

Each time Pete McCloskey takes his wife to the Alzheimer’s drug study she joined seven months ago, he does the same thing to get her ready. It’s a routine Rochelle barely remembers. He raises the bedroom blinds. He switches on the television. He tells his wife it’s the day they have to see Dr. Ross, the day she gets a shot. When he leaves the room, she may begin to shower or she may stay put, too sleepy or too absorbed in the TV to get going.

Rochelle McCloskey is one of nearly 100 patients participating in more than a half-dozen clinical trials at Ross’ three memory centers. Nationally, fewer than 1 percent of those who are eligible to enroll in a clinical trial in the United States do so, according to national statistics. Recruitment becomes even more challenging when the trials involve drugs to treat Alzheimer’s.

"Most patients are older, and simply getting to the trial site and making it through the rigors of the trial itself is a challenge," said Thies, of the Alzheimer’s Association. "It’s not unique, but it’s heightened."

As the recruitment process drags out, studies stall and results are delayed. In fact, 80 percent of all drug trials are delayed 90 days or more because enrollment hasn’t reached its quota, according to Paul Gilbert, chief executive officer of MedAvante, a company that helps run clinical trials. For current Alzheimer’s trials, Thies estimates there is a need for nearly 8,000 subjects.

"Lots of people would volunteer if a medicine would make them better," he said. "In a clinical trial, it may or may not make them better."

Ross lays the blame, at least in part, on fear.

"It’s the most stigmatized word in the medical language, the No. 1 dreaded disease," he said.

To rehabilitate attitudes toward the disease, Ross has a simple suggestion: to honor one of the first to bring Alzheimer’s out of the shadows.

"Why not rename it Reagan’s disease?" he said, after the former president.

IN SICKNESS AND HEALTH

In early July, Rochelle McCloskey marked her sixth month in the study at Ross’ Eatontown center. "Static" and "stabilized" are the words her doctors use to describe her current condition.

More than anyone else, Pete McCloskey understands the ebb and flow of his wife’s life, how, piece by piece, small details, bits of conversations and familiar facts keep slipping away.

"It makes me feel sad," he said, "Part of her is missing."

McCloskey realizes not every caregiver would be able to endure the demands of a clinical study.

"If you as the caregiver don’t perceive any improvement, you might say, ‘Let’s get out of this,’ " he said. "It’s wearing."

This is precisely what Ronald Petersen, director of Mayo Clinic’s Alzheimer’s Disease Research Center, fears most.

"The biggest threat to clinical trials is a lack of participation or subjects who leave a study prematurely."

View full sizeRochelle McCloskey is enrolled in a Genentech drug study for Alzheimer's patients at the Memory Enhancement Center in Eatontown. McCloskey is studying four words on a piece of paper as part of a cognitive test. She is being treated for early Alzheimer's.

Pete McCloskey, who turns 80 this month, is committed to seeing the trial through. He also expects his caregiving responsibilities will intensify as his wife’s condition worsens. One day, she may have to go to a long-term facility. During the past year, he has continued to juggle his roles as trustee for a local, nonprofit hospital and as a member of the Freehold Township zoning board. But he thinks he might relinquish his seat on the zoning board soon. Even though his wife’s sister and his 47-year-old son live with them, he is still the lead caregiver.

"It keeps me from doing things that I might otherwise do," he said, but he’s determined to make good on a promise he made decades ago.

"When we got married, I signed on to take care of her through illness and through health. This is part of the deal."

GLIMMERS OF HOPE

The end of the crenezumab trial is still 18 months away. Only then will the McCloskeys learn whether Rochelle was on the drug or a placebo. If the results of the trial prove as dismal as those for bapineuzumab, it won’t really matter.

"When you see these decisions (to end trials) being made by companies, it’s disconcerting," said Petersen of the Mayo Clinic. "The general public may infer that there’s nothing that works and become disillusioned."

There are, however, a few hopeful signs on the research horizon. Gammagard, manufactured by Baxter, a small drug company in Illinois, is in late-stage trials. Last month, the company revealed its immunity-boosting drug appeared to stabilize the disease in a very small sample of four patients with mild to moderate Alzheimer’s. While the patients did not recover lost cognition or function, they did not decline, either, over a period of three years. Results from a larger sample in the Gammagard trial are expected next year.

Merck is working on something called a BACE inhibitor, which also targets amyloid plaque, and results from late-stage trials of Eli Lilly’s solanezumab, another immunotherapy, could be announced next month.

If, however, crenezumab and solanezumab, like bapi, fail, the well of late-stage Alzheimer’s drugs will be nearly empty, and it will likely be years, not months, before the pharmaceutical industry makes a significant breakthrough.

On average, drug companies need 15 years and more than a billion dollars to develop a single new medicine, with no guarantee that in the end they will have a miracle drug and not a dud.

The Newmans’ gamble on bapineuzumab did not pay off. The McCloskeys can only wait to see if theirs will.

"My hope was that we might get the real medication and it might help," said Pete McCloskey. "It was only a hope."

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