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Stop the Bleeding: Can Gene Therapy Finally Cure Hemophilia?

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between 2 and 11 percent of normal levels of Factor IX. That might not seem like a big deal, but raising factor function to between 5 and 10 percent of normal turns a case of severe hemophilia into a mild one. “We believe that if you exceed 5 percent, you have a drug,” says UniQure’s (NASDAQ: QURE) CEO, Jorn Aldag.

As UniQure chief medical officer Christian Meyer says, such a seemingly small improvement could “eliminate” the risk of a spontaneous bleed. (UniQure licensed a genetic tool used in the St. Jude’s/UCL study for its own work.)

Four of the six patients in the study had been suffering from some 20 bleeding events per year before the treatment. The therapy ended those spontaneous bleeds and had lasted as long as 16 months at the time the study was published.

The results weren’t perfect, however. The therapies have now lasted as long as four years, but more than half the patients in the study have had to take a short course of the steroid prednisolone to fend off the type of immune response High first saw more than 10 years ago.

Still, the NEJM paper proved a gene therapy could get patients to “clinically important” levels of Factor IX through a simple injection into a peripheral vein, as Carter says. Mills remembers getting a number of phone calls, from investors and large pharma companies, trying to find the source of the data and where the technology came from.

“It was a huge turning point for the field,” Mills says.

Indeed, the race for AAV rights began. Here’s how all the entrants found their niche:

—Baxter is using AAV8 for hemophilia, which it acquired by purchasing Chatham Therapeutics. Chatham had licensed AAV8 from GSK/RegenX.

—UniQure is using AAV5 for hemophilia, which it licensed from the NIH in September 2011. In 2010, it grabbed rights to the therapeutic gene used in the St. Jude’s/UCL study.

—Spark is making its own AAV vectors in-house but won’t discuss details. It’s working with Pfizer on a treatment for hemophilia B.

—Dimension was formed by Fidelity Biosciences and RegenX in October 2013; the startup has a license to RegenX’s AAV vectors, and is teaming with Bayer on a gene therapy for hemophilia A.

—BioMarin licensed a hemophilia A program from St. Jude’s/UCL in February 2013.

Jorn Aldag

UniQure CEO Jorn Aldag

The differences between these groups are very technical. Take vectors, for instance. UniQure is using AAV5, and its CMO Meyer contends it should stay in the body making protein for a long time because it’s less likely than AAV8 to provoke an immune response.

Then there are the genes. Some companies, like Baxter and Spark, are using mutant therapeutic genes that clot blood 8 to 12 times more strongly than normal. The original version was discovered in a young Italian man from the city of Padua. The proposed advantage: Patients can get a therapeutic effect with a smaller dose.

Others, like UniQure, BioMarin, and Dimension, are using genes that produce a normal amount of clotting factor. The proposed advantage: The results should be more predictable.

All of these arguments about the different AAV gene therapies for hemophilia are theoretical until they’re tested in people. There are many questions to answer: How durable will they be? If they wear off, would the body’s defense systems prevent a follow-up dose from working? How much factor expression is actually needed? Can they completely cure hemophilia, or just make it less severe? Will any safety issues crop up?

The door is open for other approaches. For example, one potential limitation is that AAVs might not last long in young children. As their livers grow, the AAV-modified cells might get washed out. This is an argument made by two companies using lentiviral vectors (Biogen (NASDAQ: BIIB)) and gene editing methods (Sangamo Biosciences (NASDAQ: SGMO), via a deal with Shire) for the disease. Both methods aim to create permanent fixes by passing genetic changes on to other cells. An AAV, by comparison, does its work as long as the cell it’s in stays alive.

“We think AAV vectors for gene therapy won’t provide persistent expression levels,” says Sangamo chief scientific officer Philip Gregory. “We can offer the ability to extend that long lasting [fix] right into patients who need it the most: newborns and small kids.”

John Orloff

John Orloff

Olivier Danos, Biogen’s head of gene therapy, said similar things a few months ago. Neither Sangamo nor Biogen has any human clinical data as of yet. The only glimpse from any of the competitors, so far, has come from Baxter, which last month produced its first human data—and just a very small sliver.

Here’s a summary of those data, according to Baxter R&D chief John Orloff.

—Six patients have been treated. The two at the highest two doses produced Factor IX levels of 20 percent (after five months) and 10 percent (after eight to 10 weeks). The patient at 10 percent, however, initially hit 25 percent of normal production before his liver enzymes spiked. Baxter responded with immunosuppressive steroids.

—The other four patients were treated more than a year ago at lower doses and have had “low expression,” according to Orloff. He declined to elaborate.

—Patients have been starting out with high factor expression before those levels drop and stabilize.

—All 16 patients in the study should be dosed this year; more data are coming in June.

“It’s a small cohort obviously, we have more patients to treat, so the jury is still out,” Orloff says. “But the early data would suggest that we are seeing higher expression levels than what’s been previously reported.”

The St. Jude/UCL group, by comparison, published an update to their study in November showing that a total of 10 patients have maintained factor IX levels of between 1 and 6 percent over a median of 3.2 years after therapy. In dogs, positive effects have lasted a decade. The companies using AAV vectors for hemophilia view this as proof that they can produce a lasting, meaningful effect in humans. And more data are coming. UniQure has already started its first trial. BioMarin, Dimension, Spark, and Sangamo all could follow with their first studies this year as well. (Biogen is farther behind.)

But everyone acknowledges that there’s no telling when the therapeutic effects will wane, or if gene therapy in this field has really gotten over the hump.

“That’s one of the big questions that will have to be answered,” UniQure’s Meyer says of the staying power of an AAV gene therapy.

Haugstad takes that question very seriously. She worries that children with severe hemophilia will get a glimpse of life without needles, only to have it taken away.

Kimberly Haugstad and her son, Ben.

Kimberly Haugstad and her son, Ben

“Maybe little Jimmy is 10 years old, he gets a shot, he’s good for 4 years, now he’s 14, and really is active normal young man—and [all of a sudden] he’s got severe hemophilia again,” she says. “What happens? How would we handle the psychosocial impact to families?”

It shows, despite all the progress that’s been made, just how far gene therapy still must go to get past one of its oldest nemeses. And that has Wilson, approaching his 60th birthday, feeling a bit reflective these days.

“I tell my wife that my career is starting at 60. That the field of gene therapy is now born. That it’s the beginning, it’s not the end,” Wilson says. “She said, ‘Well then, what have you been doing for 35 years?’”

His response: “Trying to figure it out!”

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One response to “Stop the Bleeding: Can Gene Therapy Finally Cure Hemophilia?”

  1. Barry L says:

    Should have been more complete color on what Sangamo Biosciences Hemo gene therapy is all about and how it is different.
    what the delay has been has not been divulged by either SHIRE or SANGAMO. My guess,,,,manufacturing in sufficient quantities to satisfy the demand. A “cure” is possible,,,,not if,,,,,WHEN