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The first human trials of this experimental, cancer-killing drug could change everything

One day in 2002, an Ohio genetics researcher looked into a microscope and saw cancer cells dying while healthy cells weren't. This might be huge.
Credit: Kareem Elgazzar/The Enquirer
Bob Rulli undergoes a transfusion of the experimental drug BXQ-350, which lasted about an hour, Tuesday, July 10, 2018, at the University of Cincinnati's Barrett Cancer Center in Cincinnati.

Properly mixed, the medicine came out as a dark brown liquid. A nurse brought the intravenous bag to the side of a recliner, where a man with brain cancer sat. The nurse hung the plump bag on a stand and prepared the treatment for delivery. The moment had arrived for BXQ-350 to meet its first human patient.

For the man, and for the medicine, the stakes could not have been higher.

BXQ-350, by Bexion Pharmaceuticals of Covington, Kentucky, is a first-of-its-kind cancer treatment, a new approach discovered, developed and tested in Greater Cincinnati. The innovative drug is made from a human protein and does something unlike any other: It weaponizes the special mechanics of cancer to destroy it, without affecting healthy cells.

That the treatment killed nothing but cancer so jarred federal regulators that they had demanded more research in animals. But on a September day in 2016 at the University of Cincinnati’s Barrett Cancer Center, brainpower and money at last brought BXQ-350 to a critical first test for government approval.

In the infusion center, the nurse asked Bob Rulli of Fort Thomas if he was ready. She aimed the needle and punctured his arm. Patient No. 1 watched his body take in the dark brown mystery.

A ‘eureka’ moment

Cancer is a scourge of southwest Ohio and Northern Kentucky. The region’s six health systems and VA hospital are expanding infrastructure to meet demand. Still, a person diagnosed today has four basic courses of treatments: chemotherapy, radiation, surgery and immunotherapy. Complicating progress are side effects, difficulties in tolerating drugs and collateral damage to healthy tissue.

All that medicine knows about cancer is a fraction of what it doesn’t know. Breakthroughs come by surprise.

The “eureka!” moment for the new treatment can be pinned to a day in 2002 in a laboratory at Cincinnati Children’s Hospital Medical Center. There, a genetics researcher named Xiaoyang Qi was studying the action of a human protein on mice.

But when he peered into his microscope, he was amazed. The protein had fused to the walls of cancerous cells, and those cells had died. The healthy cells were unaffected.

The researcher couldn’t believe it. Then he couldn’t forget it.

For years, he tinkered with the protein, building a new molecule with a remarkable talent. No matter the variety of cancer, no matter where in the body, cells treated with the molecule died.

“And," Qi said, "I’m the only one who sees it.”

At a 2006 Xavier University reception, Qi talked about his work with Dr. Kevin Xu, a senior research scientist at Procter & Gamble. Intrigued, Xu shared the data with a P&G colleague, Ray Takigiku, who found the information “mysterious, curious and interesting.”

The P&Gers decided the idea was worth the risk of a lifetime.

Credit: Kareem Elgazzar/The Enquirer
Bob Rulli meets with a nurse at the office of Dr. Richard Curry III for a check-up on his prognosis, Tuesday, July 3, 2018, at Good Samaritan Hospital in Clifton.

They went to Cincinnati Children’s Hospital to license the invention and to get seed money. They left P&G to start Bexion Pharmaceuticals and eventually moved it into a renovated carriage house on Russell Street in the shadow of Covington’s grand Mother of God Church.

The new drug was named BXQ-350 in tribute to its creator, Xiaoyang Qi.

Qi published his first paper on BXQ-350 in 2009. In later papers, after moving to the UC College of Medicine, Qi reported that the treatment packed a one-two punch. First, BXQ-350 gets into a cellular trash compactor called the lysosome and stuffs it until the structure rips open. Second, BXQ-350 makes a cancerous cell pay attention again to the natural signal to die.

Brisk pace, then, not yet

Meanwhile, Bexion Pharmaceuticals launched the drive to raise the millions of dollars to bring BXQ-350 to the regimen of clinical trials in humans under the eyes of the U.S. Food and Drug Administration. It’s a punishing mountain to climb. About 90 percent of experimental drugs fail FDA testing.

Along the way, several federal agencies gave Bexion’s work votes of confidence. In 2010, the National Cancer Institute granted $1.5 million for research. In 2013, the NCI bestowed its Bridge Award of $2.9 million. In 2015, the Small Business Administration took note of Bexion's "innovative technologies that address national priorities."

Credit: Kareem Elgazzar/The Enquirer
Ray Takigiku, President and CEO of Bexion Pharmaceuticals Inc., stands for a portrait in the company's lab, Thursday, July 5, 2018, Covington, Ky.

But in 2014, the government hit the brakes on BXQ-350.

The FDA demanded more animal studies before considering human trials. The setback meant even more fundraising just to get to human trials. Though frustrated, Takigiku said he understood the hesitation.

“Everything was new, a new mechanism, a new compound, and that just causes pause for a regulatory body that is concerned with patient safety,” he said. “They’ve never had a drug with ambitions of attacking any solid tumor with no damage to surrounding tissue.”

Bob Rulli's cancer

On the MRI scans of Bob Rulli's brain, even an untrained eye cannot miss the dark, nearly round void, a little bigger than a golf ball. That’s where cancer had grown, in the part of his brain that created thoughts about airplane engines and ways to beat a wicked break on a putting green.

His oncologists delight in observing that if you saw Rulli on the street, you’d never guess he was sick. At 66, he still is 6-foot-1, still 215 pounds thanks partly to golf-course beer, still an easygoing husband and father of two children, now rejoicing in granddaughters.

Married 41 years, Bob and Elise Rulli live so close to Bob’s college roommate, “I can hit his house with a pitching wedge.” They are famous for Kentucky Derby parties with memorable mint juleps.

In his life, Rulli rarely had so much as a cold. “Half a Tylenol, and I’m good.” The years went by, active with his family, his work, rounds of golf. He retired in 2012 from GE after nearly four decades designing aircraft engines.

The next year, he felt the strangest pain in his head. Two months later, he learned the words glioblastoma multiforme, a rare and aggressive cancer. Life expectancy: 17 months. Less than 10 percent of patients live five years.

“I was mad,” Elise said, “mad at the world.”

Bob, though, liked his odds. “I really did think somehow, we’ll beat the 17 months.”

They adapted to the cancer calendar, living, Elise said, “from one MRI to the next.”

No treatment stopped the cancer for long, not chemotherapy, not surgery that left the 1.77-inch hole in Rulli’s left frontal lobe. When another MRI showed more progression, he endured another operation to sow radiation seeds in his brain.

Yet Rulli got his 17 months, and more. He always bounced back to play golf.

“We still tease him as much as we ever did,” said Dave Bertke, Rulli’s college roommate and Fort Thomas neighbor. “Bob is an easygoing guy, he really is. Water runs off his back. I don’t know anyone who has something as serious as he does and is so calm about it.”

In late summer 2016, the tumor surged again. The Rullis consulted Dr. Richard Curry, a TriHealth brain-cancer neurologist. He offered more chemotherapy but not much hope.

Then the doctor said an experimental drug might be coming. Bob Rulli said yes.

“If it’s successful, then it’s a fairly big step,” Rulli said. “Even if it’s not successful, it’s still a big step. It’s something that would give someone three to six months, to a year, a year and a half. That’s not small potatoes.”

Game on

By then, satisfied with Bexion’s additional research, the FDA cleared BXQ-350 for Phase I trials in human beings.

The purpose of a Phase I trial is not to treat, much less cure. The goal is to find the highest dose of a drug that is safe and tolerable. For patients with the most severe disease, a Phase I trial can be the last hope.

“It’s a nod to how toxic cancer drugs are,” Takigiku says, “that you can only do the Phase I in patients who are, in effect, terminal. Yet you want them to be healthy enough so that you don’t have to wonder too much about the side effects. Is it the drug, or the disease, or something else?”

Bexion, like many small pharmaceutical firms, could not run the Phase I trial on its own. So the company contracted with edical consultancy CTI, founded in Blue Ash, Ohio, which specializes in trials for drugs to treat rare diseases.

CTI Chairman Timothy Schroeder told a June 19 breakfast of the Northern Kentucky Chamber of Commerce that his company is so bullish on BXQ-350 that when the time came to shop for a new corporate home, Bexion was a big reason CTI crossed the Ohio River for Covington.

Four sites ran the testing: the University of Cincinnati Cancer Institute, Ohio State University, the University of Kentucky and the University of New Mexico, where Dr. Olivier Rixe was principal investigator.

Overseeing the UC leg was Dr. John Morris, director of the head, neck and thoracic program and a hardened veteran of cancer-drug trials. “You always look at it with a jaundiced eye. I take a very neutral position. I make sure the trial is well-designed. This trial was well-designed.”

19 months of infusions

Dr. Trisha Wise-Draper works with patients in UC's clinical studies for cancer drugs. She explained to Rulli the mechanics of BXQ-350. The retired GE engineer listened, but not really. It wasn't an airplane.

“If it doesn’t fly, I’m not interested.”

On that day in September 2016, for the first treatment, Rulli spent the day at UC with Wise-Draper and Morris keeping vigil for bad reactions. He had none. He felt fine.

For 19 months, Patient No. 1 got a monthly infusion, the dose slowly going up to the maximum allowed under the Phase I protocol. MRIs showed the brain cancer shrinking.

Credit: Kareem Elgazzar/The Enquirer
Elise Rulli, left, and Dr. Trisha Wise-Draper, right, the physician running the clinical trial, talk before Bob's transfusion of the experimental drug BXQ-350, Tuesday, July 10, 2018, at the University of Cincinnati's Barrett Cancer Center.

All the while, Rulli played golf three times a week and shared beers after the rounds with his pals. (What’s his handicap? “My swing.”)

By spring 2018, Rulli had lived 4½ years with glioblastoma multiforme. Tough as her husband is, Elise Rulli knew what brain cancer had taken from Bob, starting with short-term memory. “I have to remind him three times where we’re going, what we’re doing,” she said. “Half the battle is staying positive.”

But in March came a hitch. That MRI indicated the tumor had grown.

Until they knew more, the doctors took Rulli off BXQ-350. For the first time, though, Rulli felt low. “I thought they meant, ‘Well, you failed. Now you’re gone.’ ”

Yet the doctors weren't gloomy. Yes, the scan suggested new growth, but the primary tumor was smaller. No one could be sure what was going on until the surgeon went in. The operation, set for May 4, forced the Rullis to cancel the next day’s Derby party.

Then the long shot came in.

The cancer wasn’t gone, but it was stable. More important, what seemed on an MRI scan like a new tumor was, in fact, a pocket of dead cancer cells.

“I always thought the drug would work,” Elise said. “He was never sick the whole time with cancer, and I just thought it would work in him. The way he got through the other procedures, I thought he would get through it.”

The surgeon, Dr. Bradbury Skidmore of the Mayfield Brain and Spine neurology practice, said that while he is happy for his patient, in the world of brain cancer, Rulli "is an outlier. He is not the norm. As a scientist, when you see one out of the norm, you know that doesn't solve all the problems."

Richard Curry, the neurologist, ordered another MRI in July. That test would decide whether Rulli could get back on BXQ-350.

Rewriting the rules

Patient No. 1’s response presented the best challenge for Bexion, Takigiku said. “We had to rewrite our protocols several times because of him.”

In Bexion's office, full of light, exposed brick and simple furniture, Takigiku stopped talking and took a moment. Clinical distance is vital in medicine, but Patient No. 1 is no lab rat.

“All of us are happy as punch for him,” Takigiku said. “It’s why we do what we do. But it’s early yet. You work in this business long enough, you see how many ways it can mess up.”

In June, Takigiku and other Bexion officials hit the road for the annual meeting of the American Society of Clinical Oncology, this year in Chicago. Rixe delivered the Phase I conclusions for the first-in-class biologic drug:

Of the 17 patients with cancer in the brain, lung, pancreas, prostate, colon, ovary and appendix, no one had a serious adverse event on BXQ-350. Seven patients lived at least three more months, and at least two even saw disease improvement. In Patient No. 1, the presentation noted, “measurable lesion reduction over time.”

Bexion now is planning for a Phase II trial, to measure the efficacy of BXQ-350 on any solid tumors in adults, and a Phase I study in children. If the FDA approves, one of the pediatric sites will be Cincinnati Children’s Hospital, where 16 years ago, Xiaoyang Qi looked in his microscope and got a surprise.

‘Cancer is very smart’

The performance of BXQ-350 in humans tantalizes researchers. Yet experience tempers optimism. It’s too early to predict whether it will be effective or who will ultimately benefit. The sheer cost of more testing is daunting. Bexion has raised about $40 million in private financing and grants. Cracking the secrets of BXQ-350 will take far more.

“God’s honest truth is: We just don’t know how it works,” Takigiku said. “We’re going to find out, I hope.”

Xiaoyang Chi, John Morris and Rulli’s doctors said that years from now, if the FDA eventually adds it to the arsenal against cancer, BXQ-350 could be used in novel combinations with the traditional weapons. They hope the drug might give patients a real edge against a widespread killer.

“We have to be smarter than cancer,” Qi said. “We can’t let cancer be smarter than us. Right now, cancer is very smart.”

Credit: Kareem Elgazzar/The Enquirer
Bob Rulli strikes a golf ball, Wednesday, July 11, 2018, at Lassing Pointe Golf Course in Union, Ky.

Go/no go

In early July came what Bob Rulli called the “go/no go” MRI. In the waiting room of Good Samaritan Hospital, filling out the usual paperwork, Bob asked Elise how many he had taken. Twelve? Twenty? They couldn’t remember.

In the hospital gown, Rulli lay still in the MRI for an hour. Then Curry, the neurologist, examined the scan and cleared Rulli to resume BXQ-350.

The next week, he did.

The day after, Rulli kept his 9:15 a.m. tee time. At the end of the round, his foursome gathered in the clubhouse for beers and the eternal debate of how many strokes to deduct and still call it golf.

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