The coagulation system is an amazing cascade consisting of more than a dozen reactions mediated by a number of compounds with names such as “factors,” “regulators,” and “cofactors.” Defects in this system result in bleeding, a condition called hemophilia.
Biblical era references describe a bleeding tendency among male children born into the same family. In the early 1800s, scientists found how the X and Y chromosomes determined the sex of offspring as well as how hemophilia is transmitted. Two factors, VIII and X, are on the X chromosome.
Since males only have one X chromosome, a defect of a critical gene on this chromosome will primarily affect males. Females would need to inherit two defective X chromosomes to express this disease, clearly rare if the incidence of the disease is rare.
There are two main types of hemophilia. The most common is hemophilia A, caused by a deficiency in the function of factor VIII, with an incidence of 1 in 5,000 births. Hemophilia B, a deficiency in the function of factor IX, is much more rare, with an incidence of 1 in 25,000 births. About 18,000 people in the United States have various forms of hemophilia, with approximately 400 babies born each year with one of the diseases.
If insufficient factor is not available or if the factor is defective, the clotting function can be partially or totally inadequate to prevent spontaneous or traumatically induced bleeding. There is no cure for hemophilia. The first effective treatments (late 1950s) consisted of fresh frozen plasma (FFP) for both A and B. FFP contained many of the proteins in the blood, including factors VIII and IX.
But because there is only a very small quantity of factor VIII and factor IX in FFP, large quantities were required to treat a bleed; this necessitated admission to the hospital for therapy. Later it was discovered that by freezing and slowly thawing plasma, a more concentrated “cryoprecipitated plasma” form of factor could be obtained. The next significant advance was when, in the 1980s, scientists discovered ways to separate factor VIII from factor IX. These discoveries paved the way for patients to treat their disease at home.
The novel approach used for the creation of this new drug is to start with factor VIII and delete the B-domain. The resulting active portion of factor VIII is fused to the Fc portion of immunoglobulin G subclass 1 (IgG1).
Because treatment required the use of a human product, many patients were exposed to HIV and hepatitis viruses until the advent of screening laws and techniques. In the late 1980s, the discovery of the way to transfer human genes into other organisms ushered in the biologic age and shortly afterward, the first clinical trials utilizing factor VIII derived with recombinant DNA were started. By 1992, two manufactured factor A products were approved by the Food and Drug Administration.
The original protocols for treatment of hemophilia were reactive: Treatment was started after a significant bleed, typically into a joint. Boys with hemophilia were cautioned to avoid virtually any physical activity and especially sports. But later studies revealed that prophylactic treatment could significantly reduce the amount of joint destruction and allow young men to participate in more physical activities.
Hemophilia treatment intervals are based on the severity of the hemophilia. People suffering from milder forms may require treatment only occasionally, prior to surgery or after trauma. Those with very low hemophilia factor levels may need infusions as often as daily, but typically about every two days, which creates a significant burden to those suffering from hemophilia. Patients have longed for a less-frequent infusion interval, but factors degrade rapidly and must be replenished often. Recently, the FDA approval of Eloctate, manufactured by Biogen Idec, has given hope to many hemophilia A patients for a much less laborious schedule.
Eloctate, a recombinant, Fc fusion protein, is indicated for the control and prevention of bleeding episodes, perioperative management, and routine prophylaxis to prevent or reduce the frequency of bleeding episodes for hemophilia A (factor VIII deficiency). The manufacturer calls it the first significant hemophilia A treatment advancement in more than 20 years.
The novel approach used for the creation of this new drug is to start with factor VIII and delete the B-domain. The resulting active portion of factor VIII is fused to the Fc portion of immunoglobulin G subclass 1 (IgG1). The body is rather stingy with IgG molecules and basically has a natural process to avoid the rapid metabolism of these proteins.
By fusing the active portion of factor VIII to the IgG1, the body treats it like other immunoglobulins and allows it to recirculate for a much longer period than natural or recombinant factor VIII.
The weight-dependent starting dose of Eloctate for an acute bleed is based on the desired rise of factor VIII, calculated from a formula in the prescribing information. For routine prophylaxis, the dose is 50 IU/kg every four days and can be adjusted based on the patient’s response. Just as a frame of reference, an empirical finding discovered that 1 IU of factor VIII per kg body weight raises the plasma factor VIII level by 2 IU/dL.
Eloctate was studied in two phase 3 trials: a pharmacokinetics study and a clinical study. The clinical study to determine safety and efficacy consisted of a multicenter, prospective, open-label trial including 165 previously treated male patients with severe hemophilia A, defined as less than 1% endogenous factor VIII activity or a genetic mutation consistent with severe hemophilia A. The study endpoints were efficacy of each of two prophylactic treatment regimens (individualized interval and fixed weekly) compared to episodic, on-demand treatments.
A total of 757 bleeding episodes, mostly spontaneous bleeds into joints, in 106 subjects were treated with Eloctate. There were also nine patients who had scheduled major surgical procedures included in the trial.
The results of the trial demonstrated that prophylactic treatment resulted in only about one tenth the number of bleeds overall, compared to on-demand treatment. Also of note is that an individualized approach is better than a fixed-interval dose. The projected annualized bleeding rates were 1.6 in the individualized prophylaxis arm, 3.6 in the weekly prophylaxis arm, and 33.6 in the on-demand arm.
The actual number of infusions per year was also much more infrequent. The National Hemophilia Foundation guidelines suggest about 150 to 180 infusions per year.
Eloctate will significantly reduce this burden. In the individualized treatment arm, 99% of subjects were able to infuse every three days or longer, 35% achieved a dosing schedule of four days or longer, and 29% achieved a dosing schedule of five days or longer. Some could be controlled by weekly infusions.
Given that most children afflicted with severe hemophilia A receive an infusion every other day, the opportunity to move to twice per week or even less often is certainly welcome. With significantly fewer bleeds, the clinical trial for Eloctate reinforced the prophylactic approach over the on-demand approach. Eloctate fulfills the promise of Tomorrow’s Medicine.