Canadian breakthrough that became the world's most expensive drug, then vanished, gets second chance

A made-in-Canada medical breakthrough that disappeared from the market because it wasn't profitable is being revived by the National Research Council of Canada (NRC).

It's the latest chapter in the saga of Glybera, the world's first approved gene therapy, which also became the world's most expensive drug after it was licensed toa Dutch company and priced at $1 million for a one-time dose.

Glybera treats arare and potentially deadly genetic disorder called lipoprotein lipase deficiency, or LPLD.Canada has the world's largest population of LPLD patients clustered in the Saguenay region of Quebec, where an ancestor with the genetic mutation settled several hundred years ago.

People with LPLD lack a critical enzyme that helps their bodies process the fat from food. There is currently no available treatment and no cure. Those with LPLDmust avoid most dietary fat to try to prevent painful and dangerous attacks of pancreatitis.

The decision to re-develop a Canadian version of Glybera is the result of a serendipitous series of events, beginning when the NRC'sdirector of research and development for translational bioscience happened to be watching CBC'sThe Nationallast November.

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Dr. Danica Stanimirovic was in the process of selecting the first project for a new federally funded program aimed at bringing rare gene and cell therapies to Canadians at an affordable price. Thenshe sawCBC's feature report telling the story ofhow Glybera was pulled from the Europeanmarket after only one commercial sale. The drug was never offered for sale in Canada or the U.S.

"That really sparked some thinking," she said."We really have the abilityto advance that."

So she picked up the phone and called Dr. Michael Hayden in Vancouver.He's thescientist at the University of British Columbiaand the BC Children's Hospital whose team developed Glybera.Hayden said he was happy to get the call.

"I was thrilled because this represented a unique response to solve a big Canadian problem, particularly for families in Quebec.And I was just thrilled that we could do something as a national effort to achieve this."

Made-in-Canada medical breakthrough

The Glybera story started at UBC in the early 1990s, when Hayden and his teamdiscovered the first genetic mutations that caused LPLD. The researchers then developed a method to fix the malfunctioning gene and allow patients to live a nearly normal life.

After doing the preliminaryresearch, the Canadian discovery was licensed to a Dutch companycalled uniQure, which took Glybera through the rigorousclinical trialandapproval process.

When the treatment was approved by the European Medicines Agency in 2012, it made headlines as the world's firstgene therapy the first treatment that could repair a faulty gene.

When it went on sale in Europe in 2015,Glybera quickly made headlines again, this time as the "world's most expensive drug,"priced at $1 millionfor the one-time dose.

Dr. Sander van Deventer,uniQure's chief scientific officer, told CBC News last year that the price was a business calculation based on the price of other drugs that treat rare diseases. Many of those drugs cost more than $300,000 per patient per year.Because Glybera is a one-time treatment thatkeeps working for years, the $1-million price seemed reasonable, he said.

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Less than twoyears later, the drug was pulled from the market after only one commercial sale. uniQure has no plans to revive the therapy.

Although Hayden discovered the gene mutation and developed the early phase of the treatment, he had no role in the commercialization of his discovery. And that meant he also had no control over the price.

"You don't determine the outcome, you don't determine its costs," he said."I'd say what went wrong is that it was very hard to be able to make sure that this got to patients at a reasonable cost."

Stanimirovic said the fact that Canada has such a large population of LPLD patients was an important factor in deciding to give Glybera a second chance.

"This gene mutation is very prevalent in Canada compared to other places in the world," she said. "For us, it was almost calling us to do something on the manufacturing side for this particular gene therapy."

LPLD is rare, affecting one or two out of every million people around the world. But inthe Saguenay region of Quebec, where the gene mutationhas been passed down through generations,the numbers are 30 times higher.Up to one in 50 people in some communities are carrying the gene mutation. Both parents must have the mutation for a child to inherit the disease.

'Astronomical' pricein 'pharma-driven model'

The ultimate goal of gene therapy is to fix a genetic problem by giving the patient a new gene. Specially engineered viruses are used to deliver therepair gene to the patient's cells. The cost of manufacturing those virusesis often cited as one reason for the high price of therapies. The need to generate pharmaceutical shareholder profits is another factor.

"[Gene therapies] areusually targeted to very smallpatient populations," Stanimirovicsaid. "It's hard to make them in a typical pharma-driven model because it drives theprice of these therapies to astronomical levels."

At its facility in Montreal, theNRChas already developed expertise in producing viral vectors thatact as the delivery system for gene therapy. Because the scientistswill be re-engineeringGlyberausing new viral vectors,and improving the therapy, any remainingpatentswill not be an obstacle,Stanimirovicsaid.

The ultimate plan is to developpublic sector manufacturing capacity to create not just an affordable version of Glybera but other gene and cell therapies as well. The total federal funding for six projects including Glyberais estimated at about $80 million over seven years.

"Our goal is to create new partnership models that will create therapies that are more accessible and more affordable," said Stanimirovic. "We hope we can do that through public partnership or public/private partnerships. So the end goal is to really, through this project, develop Canadian capacity to take on subsequent gene therapies."

Hayden called the plan a "beautiful Canadian story."

"Now we have to translate this into something that will truly be effective forpatients in a limited time frame and I'm so excited to do this."

We'vebeen fighting for 10 years with doors closed. The possibility that something is comingis encouraging, but yes, it's long.- Brenda Potter, mother of a 10-year-old withLPLD

For patients suffering from LPLD, the wait is frustrating.

Felix Lapointe, a 10-year-old from Repentigny, Que.,was fiveweeks old when his mother learned the terrible news that her son had thepotentially deadly genetic disease.

Because there is no treatment available right now, he'smanaging the disease through a strict diet to reduce the risk of dangerous pancreatic attacks. He will have to wait another five years for the first clinical trials of the re-inventedGlybera.

"We'd like it to happen tomorrow morning," said Brenda Potter, Felix's mother. "Still, we're a little used to this. We'vebeen fighting for 10 years with doors closed. The possibility that something is comingis encouraging, but yes, it's long."