Test of experimental hepatitis C remedy turns fatal for area patient, shows risk to volunteers.

When Jessica and Brian Starkey of Leavenworth County were diagnosed with hepatitis C infections last year, they didn’t have insurance coverage for treatment. But Jessica’s doctor said there was still a chance they could get help.

Researchers in Kansas City were enrolling hepatitis C patients in a national clinical trial. They offered powerful drug cocktails featuring a promising new experimental drug to kill the virus. And it was free.

The drug, which went by the code name BMS-986094, was among a growing number of experimental antiviral medications being developed to treat hepatitis C, a liver-destroying virus that infects more than 3 million people in the United States and as many as 200 million worldwide.

Current hepatitis C treatment is long, grueling and often ineffective. Researchers hope that by using the same kind of science that tamed the AIDS virus, they can make drugs that will wipe out hepatitis C with minimal side effects.

The global market is huge, estimated at $20 billion a year. And pharmaceutical industry competition is fierce to be among the first to get U.S. Food and Drug Administration approval for their drugs.

But BMS-986094 won’t be one of them. Last month, the drug was implicated in the death of Brian Starkey and the hospitalization of at least eight other people with heart and kidney damage, creating a medical catastrophe of a magnitude rarely seen in drug research.

Not much information is available, at least publicly, about how thoroughly the drug was vetted before it was put to the test in patients like Brian Starkey. But long before Starkey died, questions had been raised about early laboratory results hinting that BMS-986094 might be toxic.

International pharmaceutical giant Bristol-Myers Squibb, which spent $2.5 billion to acquire the company that created the drug, said in a statement to The Kansas City Star that it was “committed to investigating the safety events further. We are working with experts in the field to evaluate all data and are conducting studies to evaluate the potential mechanism of this toxicity.”

Bristol-Myers Squibb also said it would share its findings with the medical community and that it already has made proprietary information about BMS-986094 available to other companies developing hepatitis C drugs.

What is clear, some experts say, is that anyone volunteering for a clinical trial for a new drug should do so with eyes wide open. New drugs may cure, but the risks are real.

‘His heart was barely flickering’

Jessica Starkey, 23, went through the 12 weeks of treatment with BMS-986094 successfully earlier in the year; the last time she was tested, the virus wasn’t detectable in her blood.

But when Brian, 25, took a higher dose of the drug, things went bad. Fast.

In late July, during his fifth week of treatment, he started vomiting. He was bent over with stomach cramps. He sweated heavily and had trouble urinating. The clinical trial doctor prescribed an anti-nausea drug. When Jessica returned home with the prescription, she found Brian turning blue and purple.

After Brian was taken by ambulance to the emergency room, doctors told Jessica he was in heart failure.

“His heart was barely flickering at all,” she said.

Brian remained on life support at St. Luke’s Hospital for more than a week. He died Aug. 10.

By that time, Bristol-Myers Squibb had announced in a terse Aug. 1 statement that it had stopped giving patients BMS-986094 “based on the emergence of a serious safety issue.”

By Aug. 23, as the significance of that safety issue emerged, the company officially discontinued development of BMS-986094.

Only 113 of the study’s projected 210 patients had been enrolled. Eight percent suffered problems serious enough to send them to the hospital.

Jessica Starkey’s lawyers say they expect the number of participants in the clinical trial who are found to have heart damage will grow.

“This was a poorly designed study that caused serious injury,” said attorney Robert Hilliard. “I’m convinced that they rushed it into trials in order to get FDA approval.”

In its statement to The Star, Bristol-Myers Squibb said: “Based on our due diligence, we believed that we could develop BMS-986094 at a dose that would provide sufficient viral suppression and resistance coverage while also having an acceptable safety and tolerability profile.”

Hilliard’s firm, Hilliard, Muñoz, Gonzales of Corpus Christi, Texas, working with the Philadelphia firm of Sheller P.C., represents more than a half-dozen people so far.

They include a schoolteacher, a retired newspaper journalist and a border patrol agent, all suffering heart damage.

So far, one of their clients has sued Bristol-Myers Squibb. Janet Schaefer Vella, a 60-year-old pediatric nurse in Corpus Christi, went into heart failure about the same time as Brian Starkey.

“She was told (when she enrolled in the trial) that it wouldn’t be dangerous, that it would cure her,” Hilliard said.

Vella collapsed while working in her hospital’s intensive-care nursery and was taken to the hospital’s emergency room, Hilliard said. She now needs a heart transplant.

“She was a runner, as fit as you can be,” Hilliard said. “Now she is a walking invalid.”

A need for a cure

Hepatitis C is passed through infected blood. Contaminated needles shared by drug abusers, even a used razor, can spread the virus. Until screening tests were developed two decades ago, blood transfusions were a common source of infection.

Hepatitis C virus can remain dormant in the body for decades before attacking the liver. The disease is a leading cause of cirrhosis and the reason for about half the liver transplants done in the United States.

Until recently, the standard drug treatment for hepatitis C was a combination of interferon, which boosts the immune system, and ribavirin, which keeps the virus from multiplying. About half of patients will benefit substantially from the drugs, if they manage to stay on the yearlong regimen. That’s not always the case.

“It’s a nightmare putting patients on these drugs,” said Steven Weinman, director of the liver center at the University of Kansas Medical Center. The drugs cause muscle aches, fever, insomnia and depression.

“Getting people through the second six months is hard,” he said. “They’ve exhausted their coping capacity. I have had many people go on disability.”

That’s why Weinman and some other liver specialists have been advising patients with mild cases of hepatitis C to hold off treatment for three to five years until the new generation of antiviral drugs now under development arrives on the market.

The first two of these drugs targeting hepatitis C became available last year. They’ve already raised the cure rate, Weinman said, but come with a big disadvantage. They must be taken along with interferon and ribavirin.

But the hope is there will be new combinations of antiviral drugs with fewer side effects that don’t have to be taken with the older drugs.

“The truth is everyone in the field thinks that in five to 10 years hepatitis C will be largely cured,” Weinman said.

Weinman doesn’t think the problems with BMS-986094 will impede the progress of other antiviral drugs to counter hepatitis C. He estimated there are more than two dozen promising candidates.

But others aren’t so sure the BMS-986094 experience won’t have a negative effect.

“It’s a disaster when things like that happen,” said Stefan Sarafianos, a University of Missouri biochemist and drug researcher.

Bristol-Myers Squibb paid “an incredibly high amount of money” to acquire the drug, he said. “Because the competition was so high, they gambled. They made a bet and they lost it.”

“I wouldn’t be surprised if it affected the mindset of drug developers … toward taking risks. It slows down development.”

It’s not clear yet whether the heart problems associated with BMS-986094 apply to other similar drugs. But the FDA already has halted human studies on two drugs being developed by Idenix Pharmaceuticals Inc. that work similarly to BMS-986094.

Any red flags?

Publicly available data on laboratory tests that were run on BMS-986094 before human trials started show that relatively low concentrations of the drug killed human bone marrow cells. Drugs similar to BMS-986094 also are known to be toxic to the kidneys.

But the publicly available information about test-tube and animal tests on BMS-986094, or the preliminary tests on people, remains sketchy.

“Was there any signal at all that should have raised a red flag?” asked Michael Carome, a physician and deputy director of Public Citizen’s Health Research Group, a consumer advocacy group involved in drug safety issues.

“We don’t know a lot of important details,” said Carome, who formerly was associate director for regulatory affairs at the Office for Human Research Protections of the Department of Health and Human Services. “I assume they did more studies on animals and did tests of heart and liver tissues. A series would normally be done. The question is what else is out there looking at both short-term and long-term exposure.”

While Carome saw no direct evidence in the available data that Bristol-Myers Squibb mishandled the development of BMS-986094, “my sense is this is an unusual case to have such a large number of serious results … happening fairly quickly.”

Only a few other cases of drug research with such significant problems have come to light in recent years.

In 2006, six healthy volunteers in the United Kingdom became violently ill, screaming and writhing, shortly after receiving an injection of an experimental drug to fight autoimmune diseases. They all survived, but needed intensive care.

In 1993, five patients in a study by the National Institutes of Health died of liver failure after receiving a promising new drug for hepatitis B. Two others received liver transplants.

Often there is very limited safety data available going into the kind of clinical trial the Starkeys joined, Carome said.

And the interests of patients may not come first.

“Too many people go in thinking, ‘(A clinical trial) is going to benefit me.’ Most people have that misconception.

“But there’s a difference between treatment and research. The primary goal of research isn’t to benefit the individual but to advance the science. You are subordinate to research needs.”

But patients can be desperate. They may have run out of treatment options or money.

“They don’t hear that message.”

What Jessica Starkey hears now is the cries of her son.

Sebastian is 19 months old. He and his father were inseparable, Starkey said.

“Every time Sebastian sees someone Brian’s age, he runs to him. He cries, because he thinks it’s Daddy.”