FDA approves long-lasting hemophilia drug based on Boston Children’s technology

Getting drugs to stay in the bloodstream longer has a substantial impact when it comes to treating chronic diseases. For someone with a chronic condition that is on medication for many years—say a patient with severe hemophilia, who endures frequent infusions of clotting factors—a short drug half-life can be expensive and quality of life may suffer.

Today we bring good news: Following a successful Phase III trial, rFIXFc recently received the green light for marketing from the FDA and from Health Canada.

Developed by Biogen IDEC under the trade name Alprolix™, rFIXFc— a recombinant factor IX Fc fusion protein—is the realization of an idea first envisioned by three researchers—Wayne Lencer, MD, a researcher in Boston Children’s Hospital’s Division of Gastroenterology, Hepatology and Nutrition, and his collaborators Richard Blumberg, MD, at Brigham and Women’s Hospital (BWH) and Neil Simister, DPhil, at Brandeis University—for large protein drugs. Their idea: To extend a protein drugs’ half-life by protecting them from being ground up by cells.

In the Phase III clinical trial, published in the New England Journal of Medicine, Alprolix stayed in patients’ blood streams nearly five times longer than the standard factor IX, and dramatically reduced both injection frequency and the rate of bleeding events in patients who received the drug prophylactically.

The initial idea

In the 1990s, Lencer, Blumberg and Simister started working together on a receptor called FcRn, which helps IgG antibodies (the most common antibody in the bloodstream) cycle through cells without being degraded.

Cells frequently sample their surroundings through a process called endocytosis. Any proteins and other molecules they pull in get trafficked to and digested in a compartment called the lysosome.

FcRn, however, grabs the tail end (called the Fc portion) of any IgG antibodies the cell pulls in and directs them back to the cell surface, releasing them back into the surrounding environment.

“FcRn traffics IgGs away from the lysosome pathway and recycles them,” Lencer explains. “That helps extend the antibodies’ half-life significantly by preventing their degradation.”

The trio realized that it might be possible to extend drugs’ half-lives by attaching an IgG’s Fc portion. The thinking was that FcRn would protect any endocytosed drugs with an attached Fc end from being chewed up by the lysosome. Instead, the receptor would cycle them back to the cell surface and release them back into the bloodstream.

This Fc-fusion strategy was combined with factor VIII and factor IX to improve hemophilia treatment.

The technology was originally licensed from Boston Children’s to Syntonix--the startup company Lencer, Blumberg and Simister founded to develop and commercialize their idea—which was acquired by Biogen IDEC in 2007.

A (clotting) factor of time

Hemophilia patients rely on the replacement of their missing clotting factor, factor VIII or factor IX (depending on whether they have hemophilia A or B, respectively). Both are large protein drugs that have to be given as long, slow IV infusions. If a patient has severe hemophilia and needs to be treated prophylactically, those infusions can be pretty frequent—sometimes two or three times per week. That is in part because in children factors VIII and IX have half-lives of 8 to 15 hours and 16 to 26 hours, respectively.

“For nearly 20 years, we’ve been giving recombinant factor IX prophylactically,” says Ellis Neufeld, MD, PhD, director of the Boston Hemophilia Center and a hematologist with Dana-Farber/Boston Children’s Cancer and Blood Disorders Center, who was not involved in the research. “But it’s expensive, perishable and can only be given intravenously, and there haven’t been any new forms in more than a decade.”

The Biogen IDEC trial’s results were a pretty conclusive win for the Fc-fusion strategy. rFIXFc stayed in the bloodstream nearly five times longer than regular recombinant factor IX. Patients given rFIXFc prophylactically only needed injections every one or two weeks. And their annual rate of bleeding events was more than 80 percent lower than that of patients given rFIXFc therapeutically.

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