Hemophilia A, also called factor VIII (FVIII) deficiency or classic hemophilia, is a genetic disorder caused by missing or defective factor VIII, a clotting protein. Although it is passed down from parents to children, about 1/3 of cases are caused by a spontaneous mutation, a change in a gene.

According to the US Centers for Disease Control and Prevention, hemophilia occurs in approximately 1 in 5,000 live births. There are about 20,000 people with hemophilia in the US. All races and ethnic groups are affected. Hemophilia A is four times as common as hemophilia B while more than half of patients with hemophilia A have the severe form of hemophilia.

Genetics                                                     

The X and Y chromosomes are called sex chromosomes. The gene for hemophilia is carried on the X chromosome. Hemophilia is inherited in an X-linked recessive manner.  Females inherit two X chromosomes, one from their mother and one from their father (XX). Males inherit an X chromosome from their mother and a Y chromosome from their father (XY). That means if a son inherits an X chromosome carrying hemophilia from his mother, he will have hemophilia. It also means that fathers cannot pass hemophilia on to their sons.

But because daughters have two X chromosomes, even if they inherit the hemophilia gene from their mother, most likely they will inherit a healthy X chromosome from their father and not have hemophilia. A daughter who inherits an X chromosome that contains the gene for hemophilia is called a carrier. She can pass the gene on to her children. Hemophilia can occur in daughters, but is rare.

Symptoms

People with hemophilia A often, bleed longer than other people. Bleeds can occur internally, into joints and muscles, or externally, from minor cuts, dental procedures or trauma. How frequently a person bleeds and the severity of those bleeds depends on how much FVIII is in the plasma, the straw-colored fluid portion of blood.

Normal plasma levels of FVIII range from 50% to 150%. Levels below 50%, or half of what is needed to form a clot, determine a person’s symptoms.

  • Mild hemophilia A-  6% up to 49% of FVIII in the blood. 
  • Moderate hemophilia A. 1% up to 5% of FVIII in the blood. 
  • Severe hemophilia A.  <1% of FVIII in the blood. 

Treatment

Up to a few decades ago a considerable proportion of patients with hemophilia died prematurely because of hemophilia. Tragically, many deaths were the result of childhood injury or surgery. Over the last forty years treatment has advanced so much that the vast majority of patients today are expected to live long and active lives.

The main breakthrough in treatment occurred when coagulation factor deficiencies linked to hemophilia could be identified and then replaced, using products derived from human blood.

In the past patients used to receive whole blood or plasma infusions to control episodes of bleeding. Even though this helped, levels of clotting factors, especially factors VIII and IX, never reached the levels required for really effective blood coagulation, nor could these levels be sustained – in other words, serious bleeding was only partly treated.

Cryoprecipitate, made through the cold precipitation of frozen plasma from1965 onwards, was the first really effective treatment for hemophilia A. Freeze-dried concentrates made from human plasma containing the right levels of Factors VIII and IX became available in the late 1960s and early 1970s. Being able to keep the treatment at home and use it as required meant that patients could travel, leave the home, go to work, and enjoy a level of independence. However, a large number of patients subsequently became infected with blood-borne pathogens, such as hepatitis B, hepatitis C and HIV.

From the mid 1980s rigorous donor selection and viral inactivation procedures reduced the risk of blood-borne viral transmission to nearly zero. During the 1990s it became possible to prepare synthetic (recombinant) factors, using specially prepared mammalian cells and these recombinant concentrates are now widely used.

The main medication to treat hemophilia A is concentrated FVIII product, called clotting factor or simply factor. Recombinant factor products, which are are developed in a lab through the use of DNA technology, preclude the use of human-derived pools of donor-sourced plasma. And while plasma-derived FVIII  products are still available, approximately 75% of the hemophilia community takes a recombinant FVIII product. These factor therapies are infused intravenously through a vein in the arm or a port in the chest.

DDAVP (desmopressin acetate) is the synthetic version of vasopressin, a natural antidiuretic hormone that helps stop bleeding. In patients with mild hemophilia, it can be used for joint and muscle bleeds, for bleeding in the mucous membranes of the nose and mouth, and before and after surgery. It comes in an injectable form and a nasal spray.

Aminocaproic acid prevents the breakdown of blood clots. It is often recommended before dental procedures, and to treat nose and mouth bleeds. It is taken orally, as a tablet or liquid.

The latest drug to treat hemophilia A approved from FDA (Food and Drug Administration) is AFSTYLA (Antihemophilic Factor Single Chain), a recombinant antihemophilic factor.

afstyla-hemofilia

Afstyla is specifically indicated for use in adults and children with hemophilia A (congenital Factor VIII deficiency) for:

  • On-demand treatment and control of bleeding episodes
  • Routine prophylaxis to reduce the frequency of bleeding episodes
  • Perioperative management of bleeding

It is supplied as a powder and solvent for reconstitution for intravenous injection. Please see drug label for recommended reconstitution and dosing schedules for each indication.

The FDA approval of AFSTYLA was based on results from the AFFINITY clinical development program. AFFINITY includes two pivotal and one extension open-label multi-center studies evaluating the safety and efficacy of  the drug  in children, adolescents and adults with hemophilia A. 

The data from the AFFINITY clinical development program showed a median annualized spontaneous bleeding rate (AsBR) of 0.00 in both the adult and adolescent study as well as the pediatric study.

The median annualized bleeding rate (ABR) was 1.14 in adult and adolescent patients and 3.69 in children less than 12 years of age using AFSTYLA for prophylaxis.

Of 1,195 bleeds treated in the pivotal study (848 in adults and adolescents; 347 in children), 94 percent of bleeds in adult and adolescent patients and 96 percent of bleeding events in pediatric patients were effectively controlled with no more than two infusions of AFSTYLA weekly.

81 percent of bleeds in adult and adolescent patients and 86 percent of bleeding events in pediatric patients were effectively controlled by only one infusion.

The majority of bleeding events treated with AFSTYLA (94 percent in adults and adolescents; 96 percent in children) were rated as excellent or good.

Of the 13 adult or adolescent patients in the study who underwent surgical procedures (16 total surgeries), hemostatic efficacy of AFSTYLA  was rated as excellent (15 times) or good (once).

Side effects                                                                                                                                                                                        

AFSTYLA safety was evaluated in the largest hemophilia A pivotal clinical trial program to date (258 participants). 14 of 258 participants reported a side effectAdverse effects associated with the use of AFSTYLA may include, but are not limited to, the following:

  • dizziness
  • hypersensitivity

Mechanism of action

AFSTYLA  (Antihemophilic Factor, Single Chain), a recombinant protein that replaces the missing Coagulation Factor VIII needed for effective hemostasis,  is a single polypeptide chain with a truncated B-domain that allows for a covalent bridge to link the Factor VIII heavy and light chains.

 In AFSTYLA, the two molecular chains that make up Factor VIII are joined by a strong bond to create one molecule.

image-afstyla

                                                                             Figure 2: AFSTYLA structure

 

  1. Heavy and light chains of Factor VIII are covalently bonded into a single-chain structure.
  2. This allows increased binding affinity to VWF, protecting AFSTYLA from degradation in circulation.

 

AFSTYLA has demonstrated a higher VWF affinity relative to full-length rFVIII. VWF stabilizes Factor VIII and protects it from degradation. Activated A  has an amino acid sequence identical to endogenous FVIIIa.

Factor VIII becomes activated in your bloodstream when it needs to help create a clot and stop a bleed. Activated AFSTYLA is identical to natural Factor VIII

According to Lisa Boggio, Assistant Professor of Internal Medicine, Hematology and Oncology, Clinical Director of the Rush Hemophilia and Thrombophilia Center, and AFFINITY clinical development program study investigator, FDA’s approval of the first recombinant single-chain therapy offers long-lasting hemostatic efficacy provides an important new treatment option for patients and healthcare providers as it has been specifically designed for increased molecular stability and duration of action. 

AFSTYLA offers patients an opportunity for excellent efficacy with a strong safety profile and twice-weekly dosing–potentially helping patients to fit treatment into their active lives.”

 

COPYRIGHT: This article is property of We Speak Science, a non profit institution co-fonded by Dr. Detina Zalli (Harvard University) and Dr. Argita Zalli (Imperial College London). The article is written by Detina Zalli and Brisilda Pashaj.

 

References:

1. https://www.hemophilia.org/Newsroom/Medical-News/CSL-s-AFSTYLA-Receives-FDA-Approval-for-the-Treatment-of-Hemophilia-A

2. http://labeling.cslbehring.com/PI/US/Afstyla/EN/Afstyla-Prescribing-Information.pdf

3. http://www.medicalnewstoday.com/info/hemophilia/treatment-for-hemophilia.php

4. http://www.medicalnewstoday.com/info/hemophilia/treatment-for-hemophilia.php

5. https://www.cdc.gov/ncbddd/hemophilia/diagnosis.html

6. http://www.centerwatch.com/drug-information/fda-approved-drugs/drug/100152/afstyla-antihemophilic-factor-recombinant-single-chain

7. https://www.hemophilia.org/Bleeding-Disorders/Types-of-Bleeding-Disorders/Hemophilia-A