Better by Design: New Coagulation Products on the Horizon

Date: August 8, 2011

Scientists around the world are working to improve upon and create new therapeutic options for hemophiliacs.

By Keith Berman, MPH, MBA

The prospects didn’t look good for a male infant born in 1960 with severe hemophilia. There was nothing available to prevent terribly painful and debilitating “bleeds” into the joints and muscles. Active play, sports and other physical activities were out of the question. Without a concentrated and quickly available replacement therapy for his critical missing clotting factor, chances were that he - like those before him - would die by early adulthood from an uncontrolled internal hemorrhage. If he survived, he faced a lifetime of pain and crippling joint damage.

Less than five years later, that young boy’s odds improved dramatically. He and his parents could thank an extraordinary series of scientific and technological advances that transformed hemophilia care, and with it the lives of thousands of people with hemophilia A and B. Because of these advances, early developing bleeds can be readily managed or prevented almost entirely by self-treatment at home, using safe, purified concentrates of factor VIII (for hemophilia A) or factor IX (for hemophilia B).

Today, the drive to improve hemophilia therapy remains in high gear. Some scientists continue to pursue gene therapy - the definitive but elusive “cure” for these conditions. But, meanwhile, other scientists in labs and hospitals throughout the world are hard at work designing, developing and testing new clotting proteins that promise to resolve important drawbacks that persist with our current therapeutic options.

Hemophilia Therapy: How Far We’ve Come

While factor VIII and IX and their role in the “coagulation cascade” had been described by the early 1960s, no one had figured out how to isolate and concentrate them from human plasma. Because these clotting factors are present in plasma at very low levels, hemophilia patients suffering serious bleeds often had to further endure potentially dangerous transfusions of large quantities of plasma to get enough of the deficient protein.

Then in 1964, a Stanford physiologist named Judith Pool discovered that slowly thawing fresh frozen plasma causes it to separate into layers - and the heaviest layer on the bottom is enriched about tenfold with active factor VIII and IX proteins. Almost overnight, this cryoprecipitate, or “cryo,” prepared by blood banks became the first effective treatment for hemophilia A and B.

But cryo had a major downside. It had to be stored frozen and administered in a hospital setting equipped to deal with serious adverse reactions. The clotting factor content could vary considerably from one unit to the next. Plasma fractionators stepped in to solve these problems by pooling large numbers of donor plasma units and further refining the cryoprecipitation process to produce specific concentrates rich in factor VIII or factor IX. Their first products - freeze-dried in small vials and stable at refrigerated temperatures - were introduced in the mid-1960s.

The availability of a purified factor concentrate that could be stored in a refrigerator set the stage for the next great leap in hemophilia care. By the early 1970s, patients were self-infusing the clotting factor concentrate at home, work or school to manage a bleed as soon as possible after the first appearance of symptoms.

Aware that as little as 1 percent of the normal level of active circulating clotting factor is enough to support hemostasis, specialists in Europe tried regular frequent injections of these products in patients in an effort to prevent irreversible joint damage and other debilitating or potentially life-threatening bleeds. The efficacy of prophylactic treatment is now well-established, and it is considered optimal therapy for children and many adults with severe hemophilia A and B.

Other advances that followed in the 1980s and 1990s focused mainly on creating safer products that have all but eliminated the risk of contamination with hepatitis viruses or HIV. Today, hemophilia specialists and patients have the choice of highly purified clotting factors isolated from human plasma or produced synthetically using recombinant DNA technology.

With careful adherence to prescribing orders, people with even severe hemophilia can expect to live a normal life span with far less disability than in the era before today’s highly purified factor concentrates. But problems and unmet needs remain in hemophilia therapy. Too many injections are required to prevent or control bleeds, which can be particularly challenging for younger children. The product doesn’t work quickly enough. And, exposure to a new product sometimes triggers dangerous “inhibitor” antibodies that dramatically complicate treatment and increase its cost.

First Needs: Longer-Acting Coagulation Factors

Roughly half of people with hemophilia A and one-third of those with hemophilia B are classified as severe because of the negligible functional activity of their defective factor VIII or IX coagulation proteins.

For children with severe hemophilia, prophylaxis - usually starting at under 1 or 2 years of age - is the optimal therapy to minimize the risks of acute life-threatening bleeds and long-term disability. Many severely affected adults also are prescribed regular prophylactic injections of clotting factor to reduce the frequency of bleeds and permanent damage to ankle, knee, elbow and other joints. And, hemophilia patients who use factor concentrates only “on demand” when they experience hemorrhages into joints or soft tissues also often require multiple, frequent infusions to manage their bleeds.

Yet many patients and their adult caregivers can’t successfully manage multiple self-injections a week, or, in some cases, as often as every other day. In prophylaxis studies in children, noncompliance rates of up to 40 percent have been reported, with time and challenges of the infusions being the most common reasons. Similar problems also have been reported about adults who started on prophylaxis but later dropped out. While some resume prophylaxis after experiencing bleeds, others do not. In very young children for whom IV injections are especially challenging, a central venous access device is often implanted, adding risks of serious infection or thrombosis.

So why the need for so many injections in the first place? Very simply: The half-life of the injected factor - the amount of time for half of the injected protein to disappear from the circulation - is a mere 10 hours for factor VIII and less than 24 hours for factor IX.

In response to this, a number of competitors are now well along in development of novel factor VIII and IX products manipulated in unique ways to prolong their circulating half-life:

  • Pegylation. Novo Nordisk is now evaluating the safety of its “pegylated” recombinant factor IX (rFIX) in non-bleeding patients with hemophilia A. This concept of coating a therapeutic protein with a polyethylene glycol (PEG) has been proven to prolong the half-life of several biopharmaceuticals now licensed and available in the U.S. In a recent study in minipigs, Novo’s pegylated factor IX had more than a fourfold longer half-life than a licensed rFIX.
  • Novo has separately reported a dramatically extended half-life for an experimental pegylated version of NovoSeven, its recombinant factor VIIa (rFVIIa) used as a “bypassing agent” in hemophilia patients with inhibitors who fail to respond to conventional clotting factors.
  • For hemophilia A patients on prophylaxis, Baxter Healthcare is developing long-acting rFVIII-von Willebrand factor products that may allow as little as a single weekly injection. They incorporate either a proprietary PEG reagent or a biodegradable polymer to extend circulating half-life.
  • Liposomal encapsulation. Bayer Healthcare has found a way to encapsulate its Kogenate FS rFVIII in liposomes, which are microscopic spheric particles made of a lipid bilayer similar to a cell membrane. For good measure, they have pegylated these liposomes to further prolong the half-life of this rFVIII. A 260-patient Phase II study that started in June will determine whether once-a-week injections of the product for a full year are as effective at preventing bleeds in severe hemophilia A patients as a much higher total dose of Kogenate FS self-administered three times weekly.
  • Genetic modification. By introducing gene mutations and other design changes, Bayer scientists also have produced an rFVIIa “analogue” that they report has a fivefold longer half-life than NovoSeven in hemophilic mice. Even more intriguing, better survival outcomes in a mouse bleeding model suggest that their “Bay7” rFVIIa might be more efficacious than NovoSeven as well.
  • Fc fusion technology. Biogen Idec has genetically “fused” a recombinant factor IX molecule with the Fc portion of an antibody as a strategy to protect it from degradation and extend the time it remains in the circulation. The product is now in Phase II clinical trials, with a factor VIII version now being readied for human testing.

Better, Faster, Stealthier

Other innovative versions of factor VIIa, VIII and IX offer the promise of quicker initiation of clotting and improved efficacy over available versions. Work also is in progress on newly designed clotting proteins with reduced risk of triggering the patient’s immune system to produce destructive inhibitor antibodies.

Octapharma, for example, has developed the first human cell line to express rFVIII, acting on the principle that the fully human cell-based production could yield an rFVIII protein variant with improved function and a reduced risk of immunogenicity. All other rFVIII products developed or approved to date are manufactured using animal cell lines. Functional assays and preclinical testing results appear very encouraging, according to the company.

Most of these prospective therapeutics are based on cutting-edge science; they will be in the research pipeline for at least several more years. But like their esteemed predecessors that have vastly changed the lives of thousands of people with hemophilia, those that deliver on their promise will be well worth the wait.

Key Advances in Hemophilia Therapy

1936 Human plasma is first used to treat hemophilia.
1952 A second type of hemophilia (hemophilia B) is identified, which arises from a defect in the clotting protein now known as factor IX.
1950s Fresh frozen plasma becomes the mainstay of treatment for hemophilia, but requires hospital visits or hospitalization.
1964 A practical freeze/thaw method to produce cryoprecipitate is discovered.
1966-1968 First factor VIII and IX concentrates become commercially available.
1970s Availability of freeze-dried factor concentrates allows patients or their parents to self-infuse their product at home.
1982-1984 Human factor VIII and IX genes are cloned.
1992 First recombinant factor VIII products become available.
1997 First recombinant factor IX product becomes available.
1998-2001 Gene therapy trials for hemophilia A and B are initiated.
2000s Manufacturers introduce products with enhanced safety and usage convenience (e.g., easier reconstitution, room temperature storage, larger vial sizes).

Keith Berman, MPH, MBA, is the founder of Health Research Associates, providing reimbursement consulting, business development and market research services to biopharmaceutical, blood product and medical device manufacturers and suppliers. Berman previously worked in product development, reimbursement development and market research roles at Baxter Healthcare, Siemens Medical and MiniMed Technologies (now a Medtronic division). Since 1989, he has also served as editor of International Blood Plasma News, a blood products industry newsletter.