On the Horizon

On the Horizon

Avariety of new treatments for both hemophilia A and B are now being developed, all based on the concept of prolonging the activity of replacement factors so that fewer, less frequent infusions are needed to prevent bleeding. The furthest along the development pipeline are rFVIIIFc and rFIXFc, which were described earlier in the section, "Creating Longer-Lasting Prophylactic Therapy."

PEGylated replacement factors. Researchers are testing the safety and effectiveness of bonding replacement coagulation factors to polyethylene glycol (PEG) to make these factors last longer in the body. PEGylated drugs have been used for treating other diseases since 1990 and have proved to be both safe and well tolerated, without any loss of the drugs' effectiveness.

Hemophilia A. In a small study, 19 patients with hemophilia A started therapy with recombinant factor VIII (rFVIII) and completed treatment with a single dose of PEGylated rFVIII (BAX 855). Effective blood levels of BAX 855 lasted up to 50% longer than they did for rFVIII. Further, thrombin generation (a measure of blood-clotting activity) was observed for more than 120 hours (5 days) after infusion of the higher of two doses of BAX 855. No serious or treatment-related adverse events occurred in any of the patients, and none developed inhibitors to BAX 855. These promising results have lead to a much larger study, called PROLONG-ATE, to determine the safety and effectiveness of BAX 855 for both prophylactic therapy and treatment of bleeding episodes in patients with severe hemophilia A.

Another PEGylated rFVIII product under development, BAY 94-9027, showed improvement over regular rFVIII in its absorption, distribution, metabolism, and excretion by the body, with a half-life of 19 hours, twice that of rFVIII. BAY 84-9027 was tolerated well by the patients who received it, and it caused no adverse reactions or inhibitor development. Its safety and effectiveness currently are being tested in a multinational clinical trial (PROTECT VIII) in 134 previously treated adults and adolescents with severe hemophilia A.

A study of yet another PEGylated rFVIII product known as N8-GP showed similar results—treatment with N8-GP was effective twice as long as was conventional rFVIII without causing side effects or development of inhibitors.

Hemophilia B. Bonding recombinant factor IX to PEG (N9-GP) also is being tested. In one study, 16 previously treated people with hemophilia B were given one dose of the factor they usually used and then one dose of N9-GP. N9-GP remained effective five times longer than did the regular formulation. One person had a sensitivity reaction to N9-GP and left the study, but none developed inhibitors.

These and other results have suggested that prophylactic therapy for hemophilia B may be given as infrequently as once every two weeks. In addition, when injected on demand to stop a bleeding episode, a single dose of N9-GP could provide a sufficient level of coagulation factor IX for almost an entire day, replacing two doses of rFIX given every 12 hours.

Pegylated liposomes. Scientists also are trying to increase the length of time that recombinant factor proteins stay active by attaching them to PEGylated liposomes (artificial bubbles made up of two fat layers). The liposomes carry the factor protein and shield it from being eliminated by the body.

In an early study, 12 previously treated people with hemophilia A were given two different dosages of PEGylated liposomal rFVIII (BAY 79-4980). Although BAY 79-4980 was better tolerated than rFVIII and extended the time between bleeding episodes, later studies showed no benefit of BAY 79-4980 over standard rFVIII.

Polysialylation. Substances known as polysialic acids also may be attached to recombinant factor proteins. These substances attract water and causes a watery "cloud" to surround the protein and protect it from being broken down and eliminated from the body. Unlike PEG, polysialic acids are natural substances and are biodegradeable. Armed with this knowledge, scientists are testing polysialylation of rFVIII, rFIX, and other blood factors to see if they can lengthen their half-lives in the body without losing their effectiveness.

Fc fusion. This technology fuses replacement factors with another naturally occurring protein with a much longer half-life. Immunoglobulin G (IgG) is such a protein. This process protects the replacement factor protein from being processed by the body and allows it to remain active longer.

Hemophilia A. In the first study of this technology in humans, 16 participants were given one dose of rFVIII followed by an equal dose of rFVIII fused with the Fc portion of IgG (rFVIIIFc). These doses were tolerated well and caused no side effects or inhibitor development. Further, rFVIIIFc remained active 60% longer than did rFVIII and was eliminated from the body at half the rate of rFVIII.

In a larger study of of rFVIIIFc in 165 people with hemophilia A, early results revealed no development of inhibitors or side effects. On average, rFVIIIFc needed to be given only twice a week to prevent bleeding, and one third of the patients who received rFVIIIFc could be dosed every 5 days and still be adequately protected. When on-demand dosing was studied, one dose of rFVIIIFC controlled 87% of bleeding episodes, and one or two doses controlled bleeding in 98% of the people treated.

Hemophilia B. One study of 14 people with hemophilia B showed that increasing doses of rFIX fused with the Fc portion of IgG (rFIXFc) resulted in three times the activity of FIX than did standard factor replacement products. rFIXFc was tolerated well and caused no serious adverse effects or development of inhibitors.

Early results from a recently completed study in 123 people with hemophilia B showed good tolerance of rFIXFc in all but one of the study participants. rFIXFc stayed active for two to three times longer than did rFIX, making dosing every two weeks a possibility. Over one half of the patients given individualized dosing to prevent bleeding could wait 14 days or longer between infusions. In patients who received on-demand therapy, about 90% of bleeding episodes were controlled with just one dose of rFIXFC and 97% were controlled with one or two doses.

Albumin fusion. As with Fc fusion, albumin fusion involves fusing factor proteins to another naturally occurring carrier protein (albumin) to extend the duration of activity of the factor before it is broken down in the bloodstream.

Hemophilia B. In a first-in-human study, infusion of rFIX fused with albumin (rFIX-FP) in 25 people with hemophilia B was safe and demonstrated a half-life five times longer than that of plasma-derived or recombinant FIX. A follow-up study of rFIX-FP showed similar results. These findings suggested that weekly prophylaxis using rFIX-FP could prevent bleeding in patients with hemophilia B and that extending the interval between doses to up to two weeks was possible.

Uncontrollable bleeding. Activated recombinant factor FVIIa (rFVIIa) is used to treat surgical and nonsurgical bleeding in patients with hemophilia who have developed inhibitors to factor replacement products. Injection of albumin-linked rFVIIa (rFVIIa-FP) in 40 patients with uncontrolled bleeding was well tolerated and caused no serious adverse effects or inhibitor development. The new formulation remained active in the bloodstream about 3½ times longer than conventional rFVIIa products.

Gene therapy. In other research, doctors and scientists are looking at transferring a normal F9 gene from healthy individuals to patients with severe hemophilia B using a virus to insert the normal gene into the patients' cells. So far, 10 participants in this study have shown significant improvements. People given low or intermediate doses of the normal gene have better levels of factor IX than they did at the beginning of the study. One patient needed factor replacement less frequently, and two others were able to go without prophylactic therapy. Moreover, all of the patients given high-dose gene therapy showed great improvements in factor IX levels and no longer needed prophylaxis, but not without added risk: Those patients given low or intermediate doses had no serious adverse reactions, whereas those given high doses showed signs and symptoms of liver inflammation.

Researchers also are thinking of other ways to repair the genetic material of patients with hemophilia. In addition to the adenoviruses used in the study described here, they are testing the use of other types of viruses (lentiviral vectors) to transport genes into the cells of patients with hemophilia A who are immune to adenoviruses and manipulating genes that have been changed in specific ways (genetic variants) to stimulate the production of normal factor IX in patients with hemophilia B.

Hemophilia is a good candidate for gene therapy, because it is a caused by a mutation in only a single gene on one chromosome and requires the production of only a small fraction of normal coagulation factor to prevent or stop bleeding.

What Does This Mean for People With Hemophilia?

Great strides are being made in treating both hemophilia A and B. New technologies that fuse standard recombinant replacement factors to other molecules, such as polyethylene glycol or the natural protein albumin, have led to the development of long-lasting replacement factors that allow for longer periods between doses while maintaining the efficacy and safety of traditional replacement factors. Most of these new replacement factors are now in ongoing clinical trials.

Gene transfer is an exciting technology that to date has resulted in long-term improvement of patients with very low levels of factor IX. A new clinical trial of this therapy will start soon in adults with severe hemophilia B. However, similar successes with gene therapy in patients with hemophilia A are lagging behind.