Approved Treatments for Hemophilia
Hemophilia is a blood disorder that is characterized by a shortage of specific clotting factors that help to form blood clots and stop bleeding. The primary treatment for hemophilia is replacement therapy that supplies the clotting factors to hemophilia patients who lack them. Other approved treatments include desmopressin, antibodies, and bypassing agents.
Antifibrinolytics are medicines that promote blood clotting by preventing or slowing down a process called fibrinolysis, which is the breakdown of blood clots. They are are used as a treatment for hemophilia, in surgical procedures to prevent excessive blood loss, and for heavy menstrual bleeding.
These therapies work by preventing the breakdown of the blood clot that occurs because of already limited quantities of clotting factors. Antifibrinolytics work at different steps in the clotting process, and the exact mechanism of action varies from one antifibrinolytic to another.
Aminocaproic acid, also known as 6-aminocaproic acid or epsilon-aminocaproic acid, is a lysine derivative that inhibits plasminogen activation in the clotting process by competing with certain proteins called plasminogen activators and preventing the degradation of fibrin clots. Aminocaproic acid can also directly interact with plasmin at higher doses.
Cyklokapron (tranexamic acid) is derived from the amino acid lysine (amino acids are building blocks of proteins). The therapy is used as an antifibrinolytic for hemophilia, as well as for treating heavy menstrual bleeding under the brand name Lysteda. It binds to plasminogen in the blood clotting pathway and prevents it from interacting with fibrin, stabilizing the clot and preventing blood loss.
In some cases, patients develop resistance to treatments — usually by developing antibodies against the clotting factors that are used to treat the disease. In these cases, bypassing agents may be used. Bypassing agents are treatments that “bypass,” or circumvent, the need for clotting factor treatment. They also can be used to treat acquired hemophilia, a rare type of hemophilia in which the body erroneously develops antibodies against its own clotting factors.
FEIBA is used to treat hemophilia A and hemophilia B in patients with inhibitors. The therapy contains multiple components that are required for blood clotting, including non-activated factors II, IX, and X, proteins that make up the prothrombin complex, and active factor VII. When transfused into patients who have stopped responding to replacement therapy, FEIBA can successfully induce clotting to stop bleeding episodes.
NovoSeven treats several different types of hemophilia, including congenital hemophilia with or without inhibitors, factor VII deficiency, and acquired hemophilia. The therapy resembles human clotting factor VIIa, which promotes the production of fibrin, another protein required for clot formation. NovoSeven is different enough from human factor VIIa that patients’ antibodies are less likely to recognize it.
Obizur is used to treat patients with acquired hemophilia. It is a recombinant factor VIII derived from pigs that is synthesized by a gene that carries the instructions to make factor VIII in these animals. It mimics the functioning human factor VIII but differs slightly in structure. Therefore, it can replace the human factor VIII without being recognized and deactivated by the antibodies in the patients’ blood and help in blood clotting.
Sevenfact (coagulation factor VIIa [recombinant]-jncw) is used to treat and control spontaneous bleeding episodes in people with hemophilia A or B with inhibitors. The active ingredient in Sevenfact is an artificial form of FVII that is isolated from the milk of genetically engineered rabbits. It is then converted into its activated form (FVIIa). Because Sevenfact is engineered in the laboratory, it has the ability to bypass the inhibitors that some patients produce.
Extended Half-Life Products
Currently available replacement clotting factors are limited by their relatively short half-lives and require intravenous injections up to three times a week to maintain protective levels. The clotting factors with extended half-life have several advantages, including reduced injection frequency, increased treatment adherence, and improved clinical outcomes. Long-acting clotting factors also provide an opportunity for improved individualized treatment for hemophilia.
Albumin fusion is an approach that combines albufuse with yeast expression technology where the clotting factor concentrate is molecularly fused to albumin, a naturally occurring protein found in the blood. The technology offers a natural alternative to PEGylation. The increased half-life of albumin fusion factors means patients need less frequent administration and a lower dosage.
The fragment crystallizable (Fc) region is the tail portion of antibody molecules called immunoglobulin G1 that binds to receptors on the surface of various cell types, mediating their physiological effects. Fc fusion is an established technology. The Fc domain of antibodies has been previously fused to various molecules such as cytokines (a type of cell signaling molecule), growth factors, or other proteins to be used as research tools or therapeutic agents.
The term PEGylation describes the attachment of polyethylene glycol (PEG) — a non-toxic and non-immunogenic polymer — to a biomolecule. It is a well-established technology used to formulate medications that treat a variety of clinical disorders. PEGylated clotting factors are used to treat hemophilia patients with the goal of prolonging the half-life of factors VIII and IX.
The objective of gene therapy for hemophilia is to deliver a healthy copy of the mutated gene to cells in the body — particularly in the liver, which is where most clotting factors are produced. To deliver the genetic cargo, gene therapies commonly use viral vectors. Most gene therapies in development specifically use vectors engineered from a family of viruses called adeno-associated virus (AAV).
Hemgenix (formerly called AMT-061 or EtranaDez) is designed to provide a highly functional copy of the F9 gene, called FIX padua, to help the body make more factor IX protein. Hemgenix is an intravenous treatment that uses a harmless virus called adeno-associated virus 5 to deliver the gene to the body.
Roctavian is a one-time gene therapy that uses a modified and harmless adeno-associated virus, called AAV5, to carry and deliver a shorter but functional version of the F8 gene to cells in the liver — the body’s main producers of clotting factors. The therapy is expected to restore FVIII levels, thereby lowering the risk of bleeds, while reducing or potentially eliminating the need for routine prophylactic (preventive) replacement therapy.
Replacement therapy is one of the standard therapies used to treat hemophilia. Hemophilia patients are highly susceptible to bleeding due to a compromised cascade of clotting reactions that are necessary to “seal” injuries. Replacement therapy involves supplying the missing clotting factor to the patient from an external source. The lack or deficiencies in factor VIII, IX, and XI cause hemophilia A, B, and C, respectively, and the type of blood clotting factor the patient needs depends on the type of hemophilia they have.
Advate contains recombinant clotting factor VIII that has been made artificially in a laboratory. It’s given as an injection, usually by a healthcare professional in a hospital or clinic, but some patients can be trained to administer the therapy themselves. Advate may also be used before surgical procedures to prevent excessive bleeding. Once administered, the clotting factor contained within Advate acts to prevent bleeding episodes.
Adynovate is an injectable factor replacement therapy developed for the treatment and prevention of bleeding in patients who have hemophilia A. Adynovate is based on Advate, but the difference is that Adynovate is manufactured by attaching polyethylene glycol (PEG), a non-toxic and non-immunogenic polymer, to Advate, allowing it to stay in the blood longer.
Afstyla is a single-chain recombinant factor VIII approved to treat patients with hemophilia A. It is produced in Chinese hamster ovary cells as a single-chain polypeptide. It has increased stability in circulation and provides long-lasting protection from bleeds with twice-weekly dosing. Once activated, Afstyla is identical to natural factor VIII.
Altuviiio (efanesoctocog alfa) is a long-lasting factor VIII replacement therapy for children and adults with hemophilia A. Administered via intravenous injection, the therapy is indicated for routine prophylaxis to reduce the frequency of bleeding episodes, on-demand treatment for bleed control, and bleed management during surgery.
BeneFIX is a recombinant coagulation factor IX indicated for the treatment of hemophilia B. Administered via intravenous injection, the therapy temporarily replaces the missing clotting factor IX and is used to control and prevent bleeding episodes, as well as in surgical management.
Hemlibra (emicizumab-KXWH) is an approved treatment to manage the symptoms of hemophilia type A in people with and without factor VIII inhibitors. Administered as an under-the-skin injection, Hemlibra is a bispecific antibody that mimics the action of factor VIII by binding to both factor IX and factor X in place of the missing factor VIII.
Ixinity is a recombinant human factor IX produced in Chinese hamster ovary cells. When injected into hemophilia B patients, Ixinity replenishes factor IX levels and restores the normal blood-clotting process. Doctors recommend it for the control and prevention of bleeding episodes. It also may be used to manage blood loss during surgery.
Kovaltry (octocog alfa) is a recombinant antihemophilic factor therapy approved to manage the symptoms of hemophilia A. It is produced using cells from a baby hamster kidney cell line that have been provided with the gene for octocog alfa, a protein engineered to be identical to the full-length natural factor VIII found in the body, along with the human chaperone protein heat shock protein 70 (HSP70).
Nuwiq is a medication approved for the treatment and prophylaxis of bleeding episodes, as well as management of bleeding during and after surgery, in patients with hemophilia A. Nuwiq is made from a human cell line and does not contain any modifications, nor is it fused to any other protein. It is administered as an infusion.
Recombinate is a recombinant factor VIII that is prescribed to prevent serious bleeding episodes in cases of injury or trauma in patients with hemophilia A. It is a form of factor VIII that is synthesized in a lab in genetically engineered Chinese hamster ovary cells. The therapy is able to compensate for missing human factor VIII whenever bleeding episodes occur.
Rebinyn (nonacog beta pegol, or N9-GP) or Refixia in Europe, is a factor IX replacement treatment for people with hemophilia B. The factor IX protein in the therapy is produced in a Chinese hamster ovary cell line before the PEGylation process. During a bleeding episode, it can act like factor IX and contribute to the formation of a blood clot to stop the bleeding.
Xyntha (moroctocog alfa) is a recombinant or man-made clotting factor therapy approved to treat and prevent bleeds in people with hemophilia A. The therapy, given intravenously or into the vein, works to restore normal blood clotting.