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Stop the Bleeding: Can Gene Therapy Finally Cure Hemophilia?

Xconomy National — 

Ben Haugstad is 12 years old and loves Taekwondo. He’s been doing it for six years, and soon he’ll be a black belt.

He also has a severe form of hemophilia. His body doesn’t produce the machinery needed to clot blood, and at any moment a bad tumble or a bruise could quickly turn into an emergency.

Three times a week, his mother Kimberly wakes up in the morning and injects Ben with drugs that, for a short time, help his blood clot. “I never thought I’d be a nurse,” she says.

These shots are expensive, about $2,500 a dose. But they’re also life-saving. They prevent cuts from becoming disasters, and ensure that spontaneous internal bleeds don’t seep into joints or organs and cause serious problems. Ben (pictured above) can live a mostly normal life. He does his Taekwondo, participates in gym class. He’s “private” about his condition, his mother says. He doesn’t talk about it or use it as an excuse to stay home from school and miss a test. He’s only had a little joint damage here and there.

“He wants to do what he can do,” Haugstad says. “We’re actually on a six week run [without a bleed] right now, so I’m pretty excited about that.”

Sometime in the near future, Ben’s tri-weekly infusions might become a thing of the past. With gene therapy, a modified virus carrying specific genetic instructions would be infused into Ben’s body and could give him the ability to clot blood for years, perhaps for life.

You’d expect his mom, the inadvertent nurse, to jump at the thought of it. But Kimberly has a much more measured response.

“When he was born, we heard loud and clear that it was going to be three years to a cure,” she says, and her skepticism is all the more notable because she’s also the executive director of the nonprofit Hemophilia Federation of America. In a sense she’s speaking for a lot of parents, not just herself.

Kimberly has good reason to be wary of promises. The idea of gene therapy for hemophilia has been around since the 1980s, and more than 15 years ago, the first hemophiliacs volunteered for tests. Yet no gene therapy product has come close to market.

Clinical failures and high-profile safety catastrophes in gene therapy trials turned hype to dust, and eviscerated most private investment in the early 2000s. Even with the current resurgence in the field, there are many questions to answer—how long will these therapies last? how safe will they be?—before Ben or any of the 400,000 or so people with hemophilia can count gene therapy as an option.

BAXTER INTERNATIONAL
Disease target: Hemophilia B/A
Name: BAX-335 (for hemophilia B; hemophilia A program undisclosed)
Vector: AAV8
Therapeutic gene: Padua mutant Factor IX
Program origin: Chatham Therapeutics
Status: Initial data from Phase I/II clinical trial of hemophilia B reported in February; more data expected in June

UNIQURE
Disease target: Hemophilia B/A
Name: AMT-606 (for hemophilia B; hemophilia A program undisclosed)
Vector: AAV5
Therapeutic gene: Wild-type Factor IX
Program origin: St. Jude Children’s Research Hospital, NIH
Status: Started Phase I/II trial for hemophilia B In early 2015; data expected in the third quarter

DIMENSION THERAPEUTICS
Disease target: Hemophilia B/A
Name: Undisclosed; hemophilia A program partnered with Bayer
Vector: AAV, undisclosed
Therapeutic gene: Wild-type Factor IX
Program origin: RegenX Biosciences
Status: Expects to start clinical testing in 2015

SPARK THERAPEUTICS
Disease target: Hemophilia B/A
Name: SPK-FIX (for hemophilia B, partnered with Pfizer; hemophilia A program undisclosed)
Vector: AAV, undisclosed
Therapeutic gene: Padua mutant Factor IX
Program origin: The Children’s Hospital of Philadelphia
Status: Expects to begin Phase I/II trials in hemophilia B in the first half of 2015

BIOMARIN PHARMACEUTICAL
Disease target: Hemophilia A
Name: BMRN-270
Vector: AAV, Undisclosed
Therapeutic gene: Wild type factor VIII
Program origin: In-house, St. Jude Children’s Research Hospital
Status: Expects to begin clinical testing in “early” 2015

SANGAMO BIOSCIENCES/SHIRE
Disease target: Hemophilia B/A
Name: Undisclosed
Strategy: Gene editing via zinc finger nucleases
Program origin: In-house
Status: Plans to submit IND in the second quarter of 2015

BIOGEN IDEC
Disease target: Hemophilia B/A
Name: Undisclosed
Vector: Lentivirus
Therapeutic gene: Undisclosed
Program origin: San Raffaele – Telethon Institute for Gene Therapy (TIGET)
Status: Potential first trial in 2016

Beyond hemophilia, gene therapy is definitely back. Startups are forming again; some have gone public. Big Pharma is investing via partnerships and strategic alliances. One product is approved in Europe—the first in a Western country—for a rare liver disorder; another might help cure a crippling blood disorder, beta thalassemia.

Gene therapies for hemophilia are farther behind, with just one developer so far, Baxter International (NYSE: BAX), reporting the barest of clinical data. (Xconomy has learned more about those data, which we will describe later.)

Following Baxter are several more companies—see the box at the right—and their clinical progress this year and next should be a touchstone for all of gene therapy. And hemophilia could prove to be the most competitive gene therapy race to date.

“The history of gene therapy really follows the story of hemophilia,” says James Wilson, the head of gene therapy research at the University of Pennsylvania, one of the field’s pioneers and most controversial figures.

Judging by the scrum of companies now with clinical trials or about to start, the story is about to add a wild new chapter. Seven groups have emerged so far with hemophilia programs. They are a mixed bag of big pharma companies protecting profitable franchises and smaller biotechs either working with the big companies or looking to one-up them.

What’s more, there are several scientific approaches and strategies involved, as well as the gamesmanship one might expect from a heated race.

“I think the competition is great,” says Wilson, who is also the scientific founder of the Washington, DC-based gene therapy startup RegenX Biosciences. “You know who’s going to really benefit from this? The patients.”

If it happens, that benefit would be a long time coming—even if patients today are better off than they were a generation or two ago. Until the 1980s, hemophiliacs who bled were rushed to the hospital and infused with a concentrated form of the “clotting factor,” or protein, that their bodies don’t produce: Factor VIII, for patients with hemophilia A, and Factor IX for those with hemophilia B.

Hospital stays could last for weeks or months if the bleed was severe, and patients understandably were overly cautious.

Worse, the infused factors came from donated blood samples and sometimes left hemophiliacs infected with HIV or hepatitis C.

The first breakthrough came when scientists genetically cloned Factor IX in 1982, and Factor VIII two years later. This led to the development of recombinant, or genetically engineered factors. The first was a Factor VIII product called … Next Page »

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  • Barry L

    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