Hemophilia has been recognized for thousands of years. A second century collection of Jewish rabbinical writings describing Jewish laws and traditions allowed for a waiver from circumcision if two brothers of a newborn had previously died after circumcision. This reference is thought to be the first description of what we now call hemophilia.
Thomas Morrow, MD
In 1803, John Conrad Otto, a distinguished Philadelphia physician, published an article describing a familial hemorrhagic bleeding disorder affecting primarily men, which outlined data he collected, by looking at nearly 90 years of a family’s inheritance pattern. A decade later, John Hay published his theory in the New England Journal of Medicine that affected men could pass the trait for a bleeding disorder to their daughters but the daughters were unaffected. This is the first published reference to an X-linked genetic disorder. In 1828, Friedrich Hopff, a student at the University of Zurich, and his professor, Dr. Johann Lukas Schönlein, first coined the term haemophilie—which means “love of blood”—that became the name we now use for a group of inherited bleeding disorders.
The first glimmer of a real understanding of the biochemical causes of hemophilia occurred in the 1920s when factor I deficiency, the first of the factor deficiencies, was described. That discovery opened up a flood of research. Over the next 40 years, scientists filled in the blanks and a good understanding of the clotting cascade—also called the coagulation cascade—emerged.
Our bodies have an amazingly complex process to decrease bleeding. It starts with rapid vasoconstriction, which slows the blood flow to the wound. A physical plug in the form of a blood clot works to stop the bleeding. Eventually, the clot gets broken down and normal vascular function returns. This is a very simple description of a wonderfully complex orchestration of literally dozens of different compounds and receptors, each step dependent on many others, all of them working in the right sequence. The players have a variety of names, but historically 13 of the identified chemicals were named “factors” and numbered, so we have factor I, factor II, factor III, and so on, up to factor XIII.
The coagulation cascade
Source: By Joe D - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=1983833
The two most common forms of hemophilia are inherited and are named hemophilia A and hemophilia B. Hemophilia, which is sometimes called classic hemophilia, is the result of a deficiency of factor VIII. It occurs in about one in every 5,000 to 10,000 male births. Hemophilia B is the result of a deficiency in factor IX and is rarer than hemophilia A, occurring in about one in 25,000 to 30,000 male births. Hemophilia B is sometimes called Christmas disease after Stephen Christmas, who had the first fully characterized case. The “royal disease” is another moniker because Queen Victoria is believed to have been a carrier of the hemophilia B gene and passed on the deficiency to many royal families in Europe through her daughters and granddaughters, most consequentially to Alexandra, who married Tsar Nicholas of Russia.
Both genes coding for factor VIII and factor IX are on the X chromosomes, so they probably won’t cause hemophilia in a female who has another unaffected X chromosome. Among the male offspring of a female “carrier” half, on average, will inherit the affected X-linked gene and, as a result, have hemophilia. Noninherited mutations can cause hemophilia, but that’s a rare occurrence.
I am going to focus on hemophilia A and factor VIII deficiency in this article because of the recent FDA approval of an exciting new way to treat the disease.
Immune system trigger
Starting with a short explanation of the role of factor VIII will be helpful in understanding hemophilia and this new treatment.
Factor VIII is an important matchmaker in the coagulation cascade. Once the clotting process is underway after, say, a laceration, it physically connects factors IX and X.
Once factors IX and X are attached, they allow prothrombin to change to thrombin, the primary component of the actual clot. If there is a shortage of factor VIII, the coupling of factors IX and X cannot occur, so there is no thrombin to form a clot and the bleeding does not stop.
Traditionally, factor VIII deficiency has been treated with replacement of either naturally occurring factor VIII, isolated from pooled human blood, or recombinant factor VIII, created by genetically modified living cells.
But because factor VIII is a protein, it triggers the immune system of some patients to unleash antibodies that destroy or inhibit factor VIII. When this occurs, the condition is termed “hemophilia with inhibitors.” Once inhibitors are present, treatment becomes very complex and is accompanied by numerous challenges. In mild cases, increasing the amount of infused factor VIII may suffice. In more severe ones, “bypass therapy” with activated prothrombin complex is used. Another approach is to use massive amounts of factor VIII to try to eradicate the inhibitor by “training” the immune system to tolerate the exogenous factor VIII.
Both of these approaches have significant costs both medically and financially. In fact, a study conducted by Optum found that the cost of treating those with inhibitors is $500,000 more per year than those without inhibitors across all ages and nearly $700,000 per year more for children. The cost of bypassing agents alone amounts to $300,000 per year.
Union of factors
Scientists have long searched for a new solution. Genentech researchers came up with the idea of using a custom-designed antibody to create the union of factors IX and X instead of depending on factor VIII to do the job. Remember that antibodies have two arms, like the letter Y, and each can attach to another molecule. By picking a proper attachment site, an antibody can actually pull together the two active locations of factors IX and X to cause the clot to form.
This research was successful and late last year, the FDA approved Hemlibra (emicizumab-kxwh), “a bispecific factor IXa- and factor X-directed antibody indicated for routine prophylaxis to prevent or reduce the frequency of bleeding episodes in adult and pediatric patients with congenital factor VIII deficiency with factor VIII inhibitors.”
The recommended dose is 3 mg/kg by subcutaneous injection weekly for four weeks, then 1.5 mg/kg once weekly. On the safety side, the label for the drug comes with a warning that Hemlibra interferes with laboratory coagulation tests and thus physicians need to be cautious when interpreting these tests.
From the patient’s perspective, Hemlibra demonstrated injection site reactions in 19% of patients, an adverse event common to antibodies. Hemlibra was also associated with headache (15%) and arthralgia (10%) as the most common adverse reactions. In 1.6% of patients, thrombotic microangiopathy was reported for those who received the bypass agent activated prothrombin complex concentrate (aPCC), causing the FDA to issue a warning of caution if the use of aPCC is being considered or has been recently used when faced with a decision to administer Hemlibra.
The efficacy of Hemlibra was determined in two clinical trials, HAVEN 1 and 2. HAVEN 1 was a randomized, multicenter open-label clinical trial with 109 adult and adolescent males, ages 12 to 75 with the established diagnosis of hemophilia A with factor VIII inhibitors who had previously received either episodic (on demand) or prophylactic treatment with bypassing agents.
The studies had numerous arms, but suffice it to say that the various arms compared the use of Hemlibra as a prophylactic agent against no prophylaxis. Efficacy was evaluated based on annualized bleeding rates (ABR) requiring treatment with coagulation factors among patients previously treated with episodic bypassing agents who were randomized to Hemlibra prophylaxis. The trials also evaluated the efficacy of weekly Hemlibra prophylaxis in reducing the number of all bleeds, spontaneous bleeds, joint bleeds, and target joint bleeds as well as patient-reported symptoms and physical functioning.
The results were nothing short of remarkable. Hemlibra demonstrated an 87% reduction in treated bleeds, 80% reduction in all bleeds, 92% reduction in treated spontaneous bleeds, 89% reduction in treated joint bleeds, and 95% reduction in treated target joint bleeds.
Moreover, when comparing Hemlibra to previous bypassing agent use, the ABR for Hemlibra was 3.3 bleeds compared to 15.7 for the bypassing agent prophylaxis; Hemlibra won hands down. The percent of patients with “zero” bleeds was 71% for Hemlibra and 12% for bypassing agents. In HAVEN 2, the most remarkable result was a 99% reduction in bleed rate in those treated with Hemlibra prophylaxis and again, a “high” (85%) zero bleed rate.
Financially, health insurers may be in for a treat. The cost of Hemlibra has been set at about $480,000 for the first year and $450,000 per year thereafter. That seems like a very large amount of money. But remember the Optum data, which says that in the population of patients with inhibitors, the yearly cost was $500,000 to $700,000 more than those with no inhibitors, meaning the total cost can easily exceed $1 million per year. The Institute for Clinical and Economic Review reported that treatment with inhibitors can cost up to $2.5 million. All of this suggests the possibility of significant savings. The catch is that these savings will not be there for treatment of patients without factor VIII inhibitors, and that is a population that Genentech is hoping will eventually be treated with Hemlibra.
Hemlibra demonstrates how far antibody science has progressed. Monoclonal antibodies were first developed to destroy cells, most notably cancer cells. But Hemlibra is an antibody that physically connects two clotting factors to prevent the devastating bleeds in hemophilia A patients with inhibitors. Such is the remarkable world of today’s medicine.