How can we get clotting factors to last longer in the blood?

Meat grinder protecting protein drugs from being ground up by cells clotting factors
Cells can grind up large protein drugs. A new technology may help those drugs escape and stay in the bloodstream longer.

Getting drugs to stay in the bloodstream longer is a big deal when it comes to treating chronic diseases. You see, a drug’s half-life—the time it takes for half of a given dose to be cleared from the body—determines how long its effect(s) last.

If a drug’s half-life is short—meaning it’s cleared quickly—patients will have to take the drug frequently. Given that someone with a chronic condition could be on the medication for many years—say, patients with severe hemophilia, who endure frequent infusions of clotting factors—a short half-life can translate into high cost. Depending on side effects and how the drug is administered, quality of life may also suffer.

Several years ago, 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 came up with a way to make protein-based drugs like clotting factors stay in the circulation longer: by keeping cells from grinding them up.

The first drug based on their work—a form of the factor IX clotting factor—just passed a Phase III clinical trial reported in The New England Journal of Medicine.

Endosomal traffic cop

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.

A (clotting) factor of time

IgG antibody large protein drugs improving drug half-life
Schematic of an IgG antibody. The two upright columns form the Fc end

Fast forward to last December. A research team from Biogen IDEC—which in 2007 bought Syntonix, the company Blumberg, Simister and Lencer founded to develop and commercialize their idea—announced the results of their Phase III clinical trial of a form of recombinant factor IX bound to an Fc segment, called rFIXFc. The study involved adolescents and adults with severe hemophilia B.

Hemophilia patients rely on one of two clotting factors, factor VIII or factor IX (depending on whether they have hemophilia A or B). 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.

According to Neufeld, Biogen IDEC is one of several companies working to make factors VIII and IX last longer in the bloodstream. He thinks that Lencer, Simister and Blumberg’s technology will get them to the finish line first.

“The question has been, will factor IX with an Fc end remain a good, safe clotting factor?” he says. “With this NEJM paper, it looks like the answer is yes.”

What remains to be seen is whether rFIXFc can have a real impact in the marketplace.

“Everyone is waiting to see whether the FDA will approve it and what the price will be,” Neufeld explains. “If it’s not too high, it could revolutionize the treatment of hemophilia B, because patients might never have to worry about low factor IX levels again.”