carousel brothers His Brothers KeeperThis fall, OMRF will begin clinical trials of an experimental drug for a deadly form of brain cancer. For the trials’ director, finding a new treatment for a fatal cancer is not just a moral imperative.

It’s personal.

Bong! Bong!

Every evening at 6:00 sharp, the bells sang out atop St. Joseph’s. Their booming chorus filled the five square blocks that made up Andale, Kansas, reminding its 400 or so residents that another day was drawing to a close.

Bong! Bong!

When the Kennedy children heard that pealing, they dropped everything and tore out for their old two-story frame house with the wraparound porch. Because they knew the rules.

Rule number one: Dress for dinner. Number two: Bring a vocabulary word and a debate topic, both of which you should be prepared to discuss. And number three …

Bong! Bong!

Be inside by the sixth chime. Because if you weren’t in the house by the time those bells went silent, you’d be in big trouble.

The older Kennedy boys were forever sprinting across the threshold in the nick of time. As they caught their breath—chests heaving, hands on knees—they’d look at the massive dining room table. And there, amidst the fresh-cut flowers and plates of piping hot meat and vegetables, would sit their little brother, plaid shirt tucked in, napkin in lap.

It wasn’t that John Kennedy tried to make his brothers look bad. It was simply that, even as a boy, John was careful. Careful to arrive at the dinner table on time. Careful to complete his chores. Careful to do all of his schoolwork.

John grew up in post-World War II middle America, not far from where America’s most celebrated general, President Dwight Eisenhower, had spent his formative years. But while other boys devoted countless hours to the re-enactment of epic battles against the Nazis, John preferred more bookish pursuits. When he didn’t have his nose buried in a text, he’d opt for a game of chess or the company of his fellow members of the math club.

A talented student, John earned stellar grades in high school. He secured a coveted spot in a five-year engineering program at the University of Kansas, then completed his coursework in four years. During summer breaks, he worked odd jobs and scraped together enough to pay for most of his education. After graduation, he married his college sweetheart and landed a position as a bridge designer with the Kansas Department of Transportation, where he’d spend his entire career.

The pair built a home and adopted two children. When he wasn’t busy being a father, husband or engineer, John loved to putter in the garden, cook, make wine and build wood furniture.

Through it all, he took care of things. He saved enough money to pay off the mortgage in five years. He squirreled away funds for his children’s education, for retirement, for the needs and emergencies that might one day arise. He worried and planned so that his loved ones didn’t have to.

A devout Catholic, John began each day by attending mass. It gave him strength, he said, helped to sustain him. Like the bells of St. Joseph’s in his youth, this daily rite provided the mooring for a life that seemed picture perfect.

In 1992, as he drove to a family reunion, John detected a distinctive odor. Thinking it must be coming from the car, he pulled to the shoulder to give the vehicle a look. Everything checked out. Odd, he thought as he drove away, still smelling what he could have sworn was sauerkraut.

A few weeks later, he headed home from work by his usual route. But a few minutes later he found himself miles off his intended path. He knew the route so well—he’d been driving it for 25 years. How could he have gotten so lost? He decided he’d better call a doctor.

Tests revealed a brain tumor, a massive growth that his physicians diagnosed as a glioblastoma. This cancer, even when caught early, offered a dismal prognosis. And John’s doctors said his tumor had been growing for some time. As it had spread, it had wrapped itself around a major artery in John’s brain.

With his diagnosis confirmed, John picked up the phone and dialed a familiar number. Surely his big brother Larry would know what to do next.

In the Kennedy family, Larry was the logical first source for those seeking medical advice. A microbiologist by training, he’d worked in labs studying pathogens, vaccines and even food systems for space flights. After transitioning to management, he remained in the pharmaceutical and chemical industry, serving in a variety of different roles at Burroughs Wellcome, Mallinckrodt and Schering Plough.

Still, three decades in the pharmaceutical industry could not have prepared Larry for the news. Glioblastoma, John said. Larry didn’t need to hear more. He knew the grim future awaiting his little brother.

The most common form of primary brain tumor, glioblastomas spread aggressively in and around the brain. As the tumors grow, they cause a range of symptoms: headache, nausea, vomiting, seizures, neurological deficits, and, as John had already experienced, memory loss. Ultimately, the tumors become so large that they cause cerebral edemas—excessive accumulations of water on the brain—or massive amounts of pressure within the skull. Either condition can be fatal. Without medical intervention, glioblastoma patients can expect to live three months from diagnosis. Even with treatment, most live little more than a year.

When John’s call came, Larry was working for a pharmaceutical company in Chicago. He had close ties with researchers and physicians at the University of Chicago and Northwestern University, people who would know the cutting-edge techniques that must be emerging to treat this deadly cancer. But when he talked to them, searching for some novel approach to save his brother, each essentially said the same thing: The standard course of treatment is your only option.

That treatment typically entailed removing as much of the tumor as possible, then administering radiation and chemotherapy to whatever remained of the growth, hoping to shrink it further. But by the time doctors found John’s tumor, it had firmly affixed itself to his cerebral artery, making surgery impossible. So his physicians began John’s treatment by implanting radioactive pellets in his brain. The radiation slowed the tumor’s growth, but it also crippled his immune system.

John soon developed a severe yeast infection in his throat. With his airway almost completely blocked, he couldn’t talk and could scarcely breathe. Fearing he would choke to death, doctors inserted a breathing tube to keep him alive. To treat the infection, they administered powerful antibiotics. The drugs succeeded, but at a stiff price: They also destroyed the lining of John’s throat and stomach, leaving him unable to eat without nausea and extreme gastric distress.

For 2½ years, John lived like this, the disease’s growing toll on him compounded by the harsh treatments and accompanying side effects. Finally, the tumor throttled his cerebral artery. With blood no longer able to flow to his brain, John died. He was 47 years old.

To the end, he wanted to ensure that everything was taken care of. “The last time I talked to John, I promised to look after his kids,” Larry remembers. “I told him everything would be okay.”

But what Larry really meant was, I wish I could have saved you. I wish I could have done something to stop this terrible disease.

In 1998, Larry Kennedy left Chicago and came to work at OMRF. With 30 years of experience working for pharmaceutical and biotechnology companies, he had the tools and know-how to lead the foundation’s technology transfer efforts. “Technology transfer is a fancy term for a simple idea,” he says. “Our job is to transform discoveries that OMRF scientists make in the lab into therapies that can help patients.”

At OMRF, he became the person responsible for sniffing out the projects with the greatest clinical potential. He visited labs, attended seminars and set scores of meetings with OMRF researchers, all in an effort to find those compounds that might, with the proper development, become life-saving drugs.

When Larry identified a promising candidate, he’d use the business skills he’d honed in the pharmaceutical industry to find a commercial partner to help move the discovery from OMRF’s labs to pharmacy shelves. This process involved many layers—patenting, marketing, negotiating research funding and licensing agreements—but all of them focused on a simple goal. “Every time scientists knock on my door, I know they may bring news of a discovery that will eventually save lives,” he says. “I always keep that in mind, because I know families out there are holding out hope for some new drug that will help save someone they love.”

One of the projects that offered a great deal of hope for patients and their families involved a compound known as NXY-059. In experiments involving mice, OMRF’s Dr. Robert Floyd found that the compound prevented brain injury in rodents that had suffered certain types of strokes. It even worked when researchers gave it to the rodents up to an hour after a stroke. OMRF had licensed the compound to a pharmaceutical company, which had transformed the laboratory compound into an experimental drug that it wanted to test in humans. Larry negotiated agreements that enabled those human clinical trials to take place.

By making it this far in the process, NXY-059 had already beaten long odds. “For every 5,000 potential new drugs tested in animals, only about five make it all the way to the clinical trial stage,” Larry says. But success was far from guaranteed. “Of those five drugs that begin clinical trials, only one will actually make it to market.”

Clinical trials progress through a series of phases outlined by the U.S. Food and Drug Administration. Success in early stages, which study dosage and safety, allows doctors to enlist additional participants and examine whether the drug effectively treats disease. Yet as doctors administer the drug to more and more patients, they are more likely to find it has previously unseen side effects—or fails to alleviate patients’ illness.

Doctors initiated the trials of NXY-059 by administering small quantities of the drug intravenously to a group of healthy subjects, then slowly increased the dose. When the drug showed no toxicity or side effects, they initiated another trial in healthy older subjects. Again, the drug passed.

A trio of slightly larger trials looked at the drug’s safety and efficacy when given to patients who’d suffered strokes in the last 24 hours. The stroke victims tolerated the drug well, and the compound showed indications that it offered protection against some types of brain injury that accompanied stroke. So the pharmaceutical company running the trial made a major decision: It opted to proceed to the stage known as phase III.

Phase III trials comprise the most comprehensive and expensive portion of the process. For NXY-059, doctors tested the drug in 4,700 stroke patients at more than 100 clinical centers in Europe, Asia, Africa, Australia and North America. This stage alone took two years and cost tens of millions of dollars to complete. But when biostatisticians compiled the clinical data, they came to a sobering conclusion: Patients who received the drug fared no better than those who didn’t.

The drug company announced that it was abandoning any further efforts to develop NXY-059. Stroke victims would have to look elsewhere for new treatments.

Larry had spent eight years at OMRF working to get the drug to patients. He’d negotiated and renegotiated licensing agreements and financing deals. He’d participated in countless conference calls and meetings, pored over results and strategic plans. And now all of this work seemed for naught.

A few months later, in early 2007, Floyd knocked on Larry’s door. The scientist once again wanted to talk about NXY-059.

In the wake of the failed trial, Floyd had studied the data and decided to conduct some experiments that led in a different direction. He had tried variations of the compound to treat mice with liver cancer, and the results proved to be a mixed bag; while the compound showed some promise, they fell short of convincing Floyd that he should continue.

What, he asked Larry, do you think I should do?

Not long before, another OMRF researcher, Dr. Rheal Towner, had sat in Larry’s office discussing a new “rat model” he’d developed. By altering rodents’ biological make-up so that the animals develop a particular medical condition, scientists can study the illness and find new potential avenues for treating it.

In this case, Towner had developed a model for glioblastoma, the same brain tumor that had killed Larry’s brother John. Using a powerful magnetic resonance imager that OMRF had installed, Towner could capture images of the tumors inside living animals. When Towner showed Larry the MRI images of the rat tumors, memories of a decade before came rushing back. “They looked,” says Larry, “nearly identical to John’s MRIs.”

If Floyd’s compound showed some promise for treating one form of cancer, Larry realized, it might prove more effective against a slightly different manifestation of the disease. Go see Towner, he told Floyd. Talk to him about trying NXY-059 in his rats with brain cancer.

Towner was familiar with these compounds from his earlier work and agreed to try NXY-059 in his rats. When he administered a dose of Floyd’s stroke compound to a rat with glioblastoma, 90 percent of its tumor shrank. “We were amazed,” Towner says. “We tried it in several different rodent glioblastoma models, and in every case the tumors decreased and survival increased. It was working, and we wanted to know how.”

Again and again, the compound attacked the tumors, inflicting no perceptible damage to surrounding tissues or negative side effects on the mice. Even three months later, after administering the compound to the rats whose brains had once been riddled with cancer, the scientists found no evidence of regrowth or recurrence. The tumors had disappeared completely.

Further tests showed the compound dramatically decreased cell proliferation (spread) and angiogenesis (formation of new blood vessels), and it turned on apoptosis, the process of removing damaged cells so they can’t become cancerous. “Those are three major factors needed for a cancer drug,” Towner says. “This compound seemed to do all of them.”

Every subsequent report from Towner and Floyd fueled Larry’s hope that this compound, once pronounced a failure, could still help patients. But Larry wanted some perspective. So he went to visit with OMRF President Stephen Prescott.

Before he came to OMRF in 2006, Prescott had led the University of Utah’s Huntsman Cancer Institute. He’d worked alongside the neurosurgeons and oncologists there and seen countless cancer patients come to Huntsman for treatment. He’d also spent years studying the disease’s biological mechanisms in his lab.

Prescott listened as Larry outlined the success the OMRF team had when they’d treated the glioblastoma mice with Floyd’s compound, which they’d renamed OKN-007. Prescott examined the study data that Larry brought him. I think we really have something here, he told Larry. But to find out for sure, let’s ask an expert in human glioblastoma.

Prescott put the team in touch with Dr. Randy Jensen, a cancer specialist and professor of neurosurgery at Huntsman. When Jensen examined the data, he not only agreed with Prescott’s assessment—he invited Towner to come work with him in Utah for three months to more closely examine the compound and its capabilities. There the two tested OKN-007 in increasingly aggressive models of the disease Jensen had created. Again, the compound passed with flying colors. And it was in Utah that Towner first encountered people suffering from brain cancer.

“I had talked to patients on the phone, but I’d never come face-to-face with someone battling glioblastoma,” he says. “After observing them in Dr. Jensen’s clinic and watching some of the surgical procedures, it really sank in that perhaps we could provide some hope to human glioblastoma patients.”

The drug development business is risky and expensive. A small research institute like OMRF lacks the resources to bring a discovery all the way from the laboratory to the clinic. So when OMRF scientists make a promising discovery, Larry seeks out a corporate partner to take a compound to market. But when Larry contacted several pharmaceutical companies about the OMRF compound, they declined.

Glioblastoma is considered a rare disease, striking fewer than 1 in 2,000 people. With such a limited population of patients, even with the promising pre-clinical results OMRF had generated, the potential return on investment simply wasn’t enough to intrigue drug companies. “It’s hard to interest a large corporation in a project that may require a huge financial outlay but produce small profits,” Larry says. “But for the families of the 13,000 who die from glioblastoma every year, profit doesn’t matter.” Larry knew precisely how they felt. “So I couldn’t give up.”

He spent weeks reviewing the data from other clinical trials and successful drug development projects, looking for ways to make this one more appealing to investors. Then one afternoon, an idea dawned on him. It’s our discovery. Why not cut out the middleman and do it ourselves?

OMRF had never before conducted a clinical trial of its own. With every other drug born in the foundation’s labs, OMRF had handed the baton to drug companies at this stage, allowing them to assume the costs and responsibilities of coordinating the trials. But this situation offered OMRF a unique opportunity.  The company that ran the failed stroke trial had returned the trial data and remaining experimental drug to OMRF. That data, which showed no significant side effects when given to 4,700 stroke patients, could form the basis of an application to the FDA—prepared at a fraction of the cost it would normally require to put together such a proposal. If the agency approved OMRF’s application, the foundation could use the drugs remaining from the stroke trial for a significant number of the cancer patients. Again, this would cut costs significantly.

“With the safety data and drug supply, we were already two steps ahead of the game,” Larry says. “If we could iron out the details, there was a good chance we could afford to do this ourselves.”

Working with Jensen and doctors at the University of Oklahoma’s Charles and Peggy Stephenson Cancer Center, Larry designed a plan for the trials. The two-year trial would start with nine glioblastoma patients at Huntsman in Salt Lake City. Clinicians would administer the compound three times a week for the first month, then follow up with an MRI to monitor changes, if any, in the tumors. If the doctors found acceptable dosage levels and safety data from the initial patients, they’d expand the trial to include patients at Oklahoma’s Stephenson Center.

Larry organized a meeting with FDA officials to discuss the data and determine the odds of trying the compound in people. Armed with laboratory results and existing data from the stroke trials, he, Towner and Jensen presented their case to an FDA panel. Submit an application for clinical trials, the FDA reps urged. We’ll watch for it.

Larry’s staff prepared the Investigational New Drug application for FDA consideration. After weeks of sorting, collating and double-checking, a small parade of dollies left Larry’s office loaded with eight boxes of documents—7,232 pages in all—headed for the FDA.

The agency maintains a 40-day window to review applications like OMRF’s. Regulators use the time to comb through the documents and request additional information, if needed. If an applicant hears nothing from the FDA, it may proceed with trials.

With only minor modifications to the application, OMRF’s 40 days came and went.

Late this fall, more than five years after Floyd first knocked on Larry’s door with an idea about using his failed stroke drug to treat cancer, OMRF expects to begin testing Towner and Floyd’s experimental compound in patients with glioblastoma. Dr. Gabriel Pardo, a neurologist and director of OMRF’s Multiple Sclerosis Center of Excellence, will serve as medical director, and Larry Kennedy will coordinate the project.

OMRF has raised approximately $750,000, enough to fund a portion of the initiative. But the foundation must still raise more funds to complete even the early stages of the trials.

“It’s a huge effort and requires real dedication to launch a trial like this,” says Floyd. “You can’t just say, ‘Let’s try this.’ It takes people believing in it and working hard to make it happen. Luckily, at OMRF, our team believes in this project.”

Still, the trial could fail. What then?

“This compound has worked well in animals, but that’s no guarantee it will work in people,” says Towner. Yet the OMRF researcher remains hopeful. “Even if we only increase a person’s survival by three to six months, that’s success. With a survival rate of just over a year, if we can add anything more to that, it’s worth the effort.”

Soon, the first glioblastoma patients will enter Huntsman’s doors looking for a miracle or, at least, a little more time on this earth. They’ll roll up a sleeve and offer an arm to the needle that will administer the first human doses of the OMRF compound. But the test for this compound will be “severe,” Larry says. “Only those individuals who’ve failed all other standard treatment will qualify for participation.” With wrecked immune systems, physical and often cognitive complications, they’ll be the sickest of the sick.

Larry thinks of his brother often as he works through the details of the project. He wonders whether John would have agreed to participate in a trial like this. After all he endured at the end, would he have taken a chance on yet one more therapy? And might it have helped him?

“I ponder those questions every time I consider the patients who’ll enter these trials,” Larry says. “They’ve already been through so much. I know, because I’ve seen it firsthand. I know the anger, the frustration, the helplessness.”

It’s been 17 years since glioblastoma took John’s life. His brother’s death still haunts Larry, but that loss has taken him down an unexpected path. Only time will tell where that roads leads. Still, for Larry, just making it this far has made all the difference.

“It’s immensely gratifying to know that I’ve been instrumental in this process.”  It’s too late for Larry to save John. But when a door closes, a window opens. And perhaps John’s struggles opened the window that led his brother to this clinical trial. To the chance to help other Johns. And maybe, just maybe, to save them. “It feels good to have hope,” says Larry. “At last, it feels good.”