There is a huge market in drug-induced Long-QT syndrome just waiting to be tapped with the right gene associations — maybe.
Billed as a small step toward the high-volume end of Long-QT testing, Genaissance Pharmaceuticals this week licensed a polymorphism from Vanderbilt University that moves the company toward establishing a genetic test for people prone to the drug-induced version of the potentially fatal syndrome.
The Familion test Genaissance offers is intended to identify people at risk for the spontaneous form of Long-QT syndrome, which affects one person in about 5,000 and can lead to Torsades de Pointes — a potentially fatal, rapid heartbeat. But many of the polymorphisms the test looks for are also implicated in the drug-induced Long QT that can affect as many as 1 to 10 percent of people taking one or more drug from a growing list of about 80 currently approved therapeutics, depending on the drug and dose, according to Ray Woosley, president of the Critical Path Institute, a partnership between the Stanford Research Institute, the US Food and Drug Administration, and the University of Arizona.
For the moment, Genaissance’s test is the only game in town, besides a few academic centers. But even with about 50 issued and pending patents related to the five main Long-QT genes, it still isn’t clear when a test will be able to identify the people most predisposed to drug-induced Long-QT — nor even whether that is possible.
“The Familion test for these rare family-specific mutations identifies about 75 percent” of people at risk for spontaneous Long-QT, said Richard Judson, Genaissance CSO. It is not known precisely what percentage of drug-induced Long QT is genetically influenced.
“It’s a huge problem,” said Woosley. “It and liver disease are the most critical issues for the drug industry in drug safety,” he said.
Of the approximately 15 drugs taken off the market in the past 10 years, nearly half were removed for causing Torsades de Pointes, Judson said. The FDA and the Pharmaceutical Research and Manufacturers Association have formed “task forces” to study the problem, he added. PhRMA’s group could not be confirmed by press time.
“Right now, what happens in drug development is just the search for the at-risk compound, and if there are signals of QT liability associated with that compound, that drug is likely in deep trouble,” said Mike Ackerman, director of the Mayo Long-QT Syndrome Clinic and Sudden Death Genomics Laboratory, and a consultant for Genaissance.
The hope is to eliminate at-risk individuals from tests and prescriptions, said Ackerman. “If these [genes] hold the answer to predicting and preventing or dealing with the pharmaceutical issue of QT liability, then you’re talking a huge, huge market,” he added.
About 50 drugs are known to cause Torsades, and a “small and increasing number are known to prolong the QT interval,” but still lack sufficient data to show whether they also cause Torsades, said Woosley. “The FDA has in the past gone on record as saying that they’ll assume that a drug that causes Long-QT will cause Torsades in some people, under some conditions,” he said. Click here to see a three lists of drugs that can trigger Torsades.
Before a drug goes on the market, the FDA requires it to pass “thorough QT trials,” in which all study patients undergo a 24-hour electrocardiograph while taking the drug. The agency doesn’t require genetic testing, although such testing should eventually be capable of capturing most people at risk for Long-QT, said Robert Temple, FDA Center for Drug Evaluation and Research Associate Director of Medical Policy, via an FDA spokesperson.
Since at least July 2003, the agency has recommended that any rare events of extreme prolongation or arrhythmia should be tested for Long-QT alleles, according to an FDA QT draft guidance. “And so, companies are writing the test into their protocols, for their QT trials, and we’ve had some samples come in,” Judson said.
“Now most FDA people will recommend that every drug going into therapy will be tested for this potential — it’s not required, but it’s sure good business,” said Woosley.
Now the Hard Part
Developing a test for drug-induced Long-QT is complicated. There is some degree of overlap between the spontaneous and drug-induced forms of Long-QT. While some people carrying one of the polymorphisms known to cause Torsades will only show symptoms after taking a certain drug, non-carriers can also develop symptoms after taking a drug, and “if you push to high doses, most of these drugs will cause Torsades in almost everybody,” said Woolsey. Drug interactions, drug susceptibility, and gender all affect the chances a person will develop the syndrome, he added.
“In [spontaneous] congenital Long-QT, there are many, many genes involved,” Woolsey said. “Most of the gene tests only confirm the diagnosis in about 50 percent of people.” The gene Genaissance licensed, patented by Vanderbilt researcher Dan Rodin, has a frequency of about 2 percent in the population, Judson said in an email.
How useful is a genetic test in identifying people at risk for drug-induced Long QT? “That really is the gazillion-dollar question,” said Ackerman, the Genaissance consultant. “About 5 to 10 percent” of drug-induced Torsades appear to be associated with the same mutations, he said. “Could, in fact, your genetic channel profile really predict a priori who is at greatest risk of having an adverse drug reaction? That we don’t know,” he said.
That kind of test will require a “portfolio” of susceptibility variants, with a person’s risk calculated through total Long-QT genotype, said Ackerman. “If we could have a genetic biomarker — or markers — that would be a substantial breakthrough,” he said. The Familion test identifies a disease-causing mutation in about 5 to 10 percent of patients who already had a sudden death event, he added.