Hemophilia A and Hemophilia B

Hemophilia A, also called Factor VIII (FVIII) deficiency or classic hemophilia, is a genetic disorder caused by missing or defective Factor VIII (FVIII), a clotting protein. Although it is passed down from mothers to children, about 1/3 of cases found have no previous family history.(2)

Treatment for hemophilia A is dependent on several factors and there is not a universal therapy that will work for all patients. Clinically, the hallmark of bleeding in hemophilia is bleeding into the joints, muscles, and soft tissues. The severity and the risk of that bleeding can be correlated to the residual factor activity that can be measured in the blood. Patients with severe disease have less than 1% residual activity, and often have zero. These are the patients who are at risk for spontaneous and traumatic bleeding. Having over 5% residual amount makes bleeding into the joints very unusual (although not inconceivable), and most bleeding is triggered only by trauma. Residual activity of 1-5% appears for the most part to prevent spontaneous bleeding, but patients can still be at risk for joint bleeds with even relatively minor trauma.(3)

The main goal of any therapy is to completely prevent bleeding. The current World Hemophilia Federation Guidelines for the Management of Hemophilia state:(5)

• Both virus-inactivated plasma-derived and recombinant clotting factor concentrates (CFCs), as well as other hemostasis products when appropriate can be used for treatment of bleeding and prophylaxis in people with hemophilia
• Prophylaxis is the standard of care for people with severe hemophilia, and for some people with moderate hemophilia or for those with a severe bleeding phenotype and/or a high risk of spontaneous life-threatening bleeding
• Episodic CFC replacement should not be considered a long-term option for the management of hemophilia as it does not alter its natural history of spontaneous bleeding and related complications
• Emerging therapies in development with alternative modes of delivery (e.g., subcutaneous injection) and novel targets may overcome the 3 of standard CFC replacement therapy (i.e., need for intravenous administration, short half-life, risk of inhibitor formation)
• The development of gene therapies for hemophilia has advanced significantly, with product registration likely in the near future
• Gene therapy should make it possible for some people with hemophilia to aspire to and attain much better health outcomes and quality of life than that attainable with currently available hemophilia therapies
• Given the ongoing advances transforming the hemophilia treatment landscape, it is important to establish systems to constantly monitor developments in emerging and gene therapies for hemophilia and make them available as soon as possible following approval by regulatory authorities

Approximately 1 in 5 people with hemophilia A will develop an antibody, called an inhibitor, to the clotting factor concentrate(s) used to treat or prevent their bleeding episodes. Developing an inhibitor is one of the most serious and costly medical complications of a bleeding disorder because it becomes more difficult to treat bleeds. Inhibitors most often appear in the first 50 exposure days of clotting factor concentrates.(3,6) The National Hemophilia Foundation classifies inhibitors as low responding and high responding in addition to low titer (less than 5 BU) and high titer (greater than or equal to 5 BU). In low responding inhibitors when the patient receives Factor VIII the inhibitor titer does not rise. These patients can be treated with higher doses of the CFC. If the inhibitor titer increases with CFC it is considered high responding. For high responding inhibitors, the situation becomes much more complicated as even large doses of infused CFC are often rendered ineffectual by the sheer potency of the antibody response.(4)

Hemophilia B, or Christmas disease, is an inherited, recessive disorder that involves deficiency of functional coagulation factor IX (FIX) in plasma. Hemophilia B is caused by a variety of defects in the F9 gene. As this gene is carried on the X chromosome, the disease usually manifests in males and is transmitted by females who carry the causative mutation on one of their X chromosomes. Spontaneous mutation and acquired immunologic processes can result in this disorder, as well. Hemophilia B constitutes about 20% of hemophilia cases. Hemophilia B may be classified as severe, moderate, or mild, based on the plasma levels of FIX (< 1%, 1-5%, 6-40%, respectively). About 50% of persons with hemophilia B have FIX levels greater than 1%.(6)

Approximately 3-5% of patients with severe hemophilia B develop alloantibody inhibitors that can neutralize FIX. These inhibitors are usually immunoglobulin G antibodies and appear after the first infusions of FIX concentrate. Both genetic and environmental factors determine the frequency of inhibitor development. Inhibitors most often appear during the first 50 times a person is treated with clotting factor concentrates, but they can appear at any time.(6,7)

Factor IX is the treatment of choice for acute hemorrhage or presumed acute hemorrhage. Recombinant factor IX is the preferred source for replacement therapy. And while plasma-derived FIX products are still available, approximately 75% of the hemophilia community takes a recombinant FIX product. The Medical and Scientific Advisory Council (MASAC) of the National Bleeding Disorders Foundation encourages the use of recombinant clotting factor products because they are safer. Patients with severe hemophilia may be on a routine treatment regimen, called prophylaxis, to maintain enough clotting factor in their bloodstream to prevent bleeds. MASAC recommends prophylaxis as optimal therapy for children with severe hemophilia B. Aminocaproic acid is an antifibrinolytic, preventing the breakdown of blood clots. It is often recommended before dental procedures, and to treat nose and mouth bleeds.(6)

Inhibitor development is the most severe complication of treatment for patients with inherited hemophilia A or B. Choice of product for treatment depends on multiple factors, including type of inhibitor (low- or high- responding), current titer of inhibitor, location of the bleed, previous response to a product, availability of clinical trial data supporting use of the products and concomitant medications (e.g., emicizumab). For high-titer inhibitors immune tolerance induction (ITI) is the best option for inhibitor eradication.(8)

If left unchecked a persistent inhibitor will present a severe burden on patients and families as the ongoing physical, emotional, and in many cases financial toll continue to intensify. Healthcare providers will often attempt to proactively stamp out an inhibitor through ITI. ITI is an approach to inhibitor eradication where the body’s immune system begins to tolerate a therapy after daily doses of factor are administered over time. The majority of people who undergo ITI therapy will see an improvement within 12 months, but more difficult cases can take two years or longer. There is a general consensus that failure of ITI is the inability to achieve successful tolerance within 2-3 years of initiation of an ITI regimen.(5)

ITI can take several months to several years to be effective. The Hemophilia Federation of America recommends that if success has not occurred within 33 months of beginning ITI and there is a lack of a 20% decrease in the inhibitor titer over a 6 month period that it is considered a failure.(9)

In the cases of high-responding inhibitors treatment is based on several components including the type of hemophilia and the nature of the bleed. During a life or limb-threatening bleeding episode physicians can remove antibodies from the body using plasmapheresis. This is only a temporary solution however as within a few days the body will produce large amounts of new antibodies. For the person with high responding inhibitors there are therapies that can effectively treat bleeds by circumventing the need to replace FVIII. These agents are commonly referred to as bypassing agents (BPAs) and include activated prothrombin complex concentrate (aPCC) and recombinant activated Factor VII concentrates (rFVIIa).(10)

Efficacy

Alhemo (concizumab-mtci) is a monoclonal antibody antagonist of endogenous Tissue Factor Pathway Inhibitor (TFPI). Through the inhibition of TFPI, concizumab-mtci acts to enhance FXa production during the initiation phase of coagulation which leads to improved thrombin generation and clot formation with the goal of achieving hemostasis in patients with Hemophilia A or B with inhibitors. The effect of concizumab-mtci is not influenced by the presence of inhibitory antibodies to FVIII or FIX. There is no structural relationship or sequence homology between concizumab-mtci and FVIII or FIX and, as such, treatment with concizumab-mtci does not induce or enhance the development of direct inhibitors to FVIII or FIX.(1)

The efficacy of Alhemo in patients with hemophilia A and B with inhibitors was evaluated in the explorer7 trial (NCT04083781), a multi-national, multi-center, open-label, phase 3 trial that investigated the safety and efficacy of Alhemo for routine prophylaxis in 91 adults (58 HAwI and 33 HBwI) and 42 adolescents (22 HAwI and 20 HBwI) male patients with hemophilia A or B with inhibitors who have been prescribed, or are in need of, treatment with bypassing agents. Eptacog alfa was the rFVIIa used in explorer7. Patients were excluded if they had a history, current signs or symptoms, or at high risk of thromboembolic events, ongoing or planned immune tolerance induction treatment, in addition to patients with planned major surgery.(1)

The trial was comprised of 4 arms, two randomized arms and two non-randomized arms:

· Arms 1 and 2: 52 patients (27 HAwI, and 25 HBwI), previously treated on-demand, were randomized 1:2 to no prophylaxis (arm 1: on demand treatment with bypassing agents) or Alhemo prophylaxis (arm 2), with stratification by hemophilia type (HAwI, HBwI) and prior 24-week bleeding rate (< 9 or ≥9)

· Arms 3 and 4: 81 additional patients (53 HAwI and 28 HBwI) treated with Alhemo prophylaxis.(1)

Treatment with Alhemo included a loading dose of 1 mg/kg on the first day and a once-daily dose of 0.20 mg/kg starting on the second day. The dose was individualized to 0.25 mg/kg or 0.15 mg/kg if Alhemo plasma concentration measured once after 4 weeks of treatment was 4000 ng/mL, respectively. Measurement of concizumab-mtci plasma concentration after 4 weeks was used to optimize the daily maintenance dose. In the trial, a total of 108 patients received their individualized dose, 1 patient on 0.15 mg/kg, 79 patients on 0.20 mg/kg and 28 patients on 0.25 mg/kg.(1)

Efficacy was evaluated in hemophilia A and B patients with inhibitors when all patients in arms 1 and 2 had completed at least 24 or at least 32 weeks, respectively), by comparing the number of treated bleeding episodes between Alhemo prophylaxis (arm 2) and no prophylaxis (arm 1). Using a negative binomial model, a ratio of the annualized bleeding rates (ABR) was estimated to 0.14 (p<0.001), corresponding to a reduction in ABR was 1.7[95%CI:1.01;2.87] for patients on Alhemo prophylaxis arm (arm 2) and 11.8[95%CI:7.03;19.86] for patients on no prophylaxis (arm 1).(1)

Safety

Alhemo is contraindicated in patients with a history of known serious hypersensitivity to Alhemo or its components or the inactive ingredients.(1)

Number

Reference

1

Alhemo prescribing information. Novo Nordisk Inc. December 2024.

2

Hemophilia A | NBDF. National Bleeding Disorders Foundation. https://www.bleeding.org/bleeding-disorders-a-z/types/hemophilia-a

3

One size does not fit all: Individualized therapy | NBDF. National Bleeding Disorders Foundation. Published February 8, 2017. https://www.hemophilia.org/educational-programs/education/online-education/one-size-does-not-fit-all-individualized-therapy

4

Kovalich D, Goto S, National Hemophilia Foundation, et al. Living With an Inhibitor: Your Guide to Managing Hemophilia With Inhibitors.; 2023. https://www.bleeding.org/sites/default/files/document/files/living-with-inhibitors.pdf

5

Srivastave A, Santagostino E, Dougall A, et al. World Federation of Hemophilia Guidelines for the Management of Hemophilia. 3rd edition. August 2020.

6

Hemophilia B | NBDF. National Bleeding Disorders Foundation. https://www.bleeding.org/bleeding-disorders-a-z/types/hemophilia-b

7

Testing for inhibitors and hemophilia. Hemophilia. Published May 15, 2024. https://www.cdc.gov/hemophilia/testing/testing-for-inhibitors-and-hemophilia.html?CDC_AAref_Val=https://www.cdc.gov/ncbddd/hemophilia/inhibitors.html

8

Medical and Scientific Advisory Council (MASAC) MASAC recommendations concerning products licensed for the treatment of hemophilia and other bleeding disorders. Document #280. August 2023.

9

Dimichele DM, Hoots WK, Pipe SW, et al. International workshop on immune tolerance induction: consensus recommendations. Haemophilia (2007), 13 (Suppl. 1), 1-22.

10

National Hemophilia Foundation Bleeding Disorders A-Z Overview Inhibitors Treatment for Inhibitors. Treatment for Inhibitors | National Hemophilia Foundation.

Final Module

Target Agent GPI

Target Brand Agent(s)

Target Generic Agent(s)

Strength

Targeted MSC

Targeted NDCs When Exclusions Exist

Final Age Limit

Preferred Status

Effective Date

8510502505D2

Alhemo

concizumab-mtci soln pen-injector

150 MG/1.5ML ; 300 MG/3ML ; 60 MG/1.5ML

M ; N ; O ; Y