Advate (octocog alfa) for hemophilia

Last updated Sept. 19, 2023, by Margarida Maia, PhD
Fact-checked by Patrícia Silva, PhD

What is Advate for hemophilia?

Advate (antihemophilic factor, octocog alfa) is a recombinant (lab-made) clotting factor VIII (FVIII) concentrate used to prevent and control bleeding in children and adults with hemophilia A.

The therapy is indicated for:

• routine prophylaxis (preventive treatment), to prevent or reduce the frequency of bleeding episodes
• on-demand treatment, to prevent and control bleeding episodes
• surgical use to manage bleeding episodes before, during, and after minor or major procedures.

Advate is given by intravenous (into-the-vein) injection. It was developed by Baxter and its spinoff Baxalta, now part of Takeda Pharmaceuticals.

Therapy snapshot

How does Advate work?

Hemophilia A is caused by a faulty or missing clotting FVIII, a protein found in blood. Without FVIII, the blood cannot clot properly to stop bleeding. As a result, people with hemophilia A may experience heavy, longer-than-usual bleeding episodes occurring either spontaneously or as a result of an injury or surgery.

Advate contains a protein called octocog alfa, which is similar to and works in the same way as the FVIII that is needed for blood to clot normally. As such, it can be used as a replacement therapy to temporarily take the place of the faulty or missing FVIII, thereby helping to prevent and control bleeding.

Octocog alfa is made through genetically engineered Chinese hamster ovary cells. These cells were genetically modified in the lab by inserting a gene that provides instructions to make the protein.

Who can take Advate?

The U.S. Food and Drug Administration (FDA) first approved Advate in 2003 for the prevention and control of bleeding episodes in people with hemophilia A.

The indication was expanded in 2011 to include its use for routine prophylaxis in children and adults with hemophilia A.

Advate is currently approved in several countries, including Canada, Australia, and a number of countries in Asia and South America.

In the European Union, Advate was first approved in 2004 for treating and preventing bleeding episodes in people with hemophilia A. The approval was extended later that year to cover all ages.

Who should not take Advate?

Advate should not be taken by people who have a known hypersensitivity or allergy to:

• mouse or hamster proteins
• any ingredients in Advate (mannitol, trehalose, sodium chloride, histidine, Tris, calcium chloride, polysorbate 80, and/or glutathione).

The treatment is not indicated for use in people with von Willebrand disease, another disease in which the blood does not clot properly.

How is Advate administered?

Advate is given as a slow infusion directly into the bloodstream. How much is given depends on the location and extent of the bleeding, as well as on the person’s body weight, and the amount of working FVIII the body is able to make (meaning, the severity of FVIII deficiency).

The concentrate is available as a white to off-white powder supplied in single-use vials containing 250, 500, 1,000, 1,500, 2,000, 3,000, or 4,000 international units (IU). It is packaged in a Baxject III reconstitution system with 2 or 5 milliliters (mL) of diluent (sterile water) for injection.

Baxject III was first approved by the FDA in 2014 to allow for an easy, one-step reconstitution process with no need to disinfect the vials. When mixed together, powder and diluent create a clear liquid that is ready to infuse within three hours of reconstitution.

For routine prophylaxis, patients should be given:

• a dose from 20 to 40 IU per kilogram of body weight (IU/kg), every other day (three to four times a week) or
• a dose aimed at maintaining FVIII levels at 1% or higher, once every three days.

For on-demand treatment, and until the bleeding is resolved, patients should receive:

• a dose from 10 to 20 IU/kg, given every 12-24 hours (8-24 hours for children younger than 6), in the case of a minor bleeding episode
• a dose from 15 to 30 IU/kg, given every 12-24 hours (8-24 hours for children younger than 6), in the case of a moderate bleeding episode
• a dose from 30 to 50 IU/kg, given every 8-24 hours (6-12 hours for patients younger than 6), in the case of a major bleeding episode.

For perioperative management of a minor surgical procedure, such as tooth extraction, a single dose of 30 to 50 IU/kg of Advate should be given one hour before surgery, and then repeated every 12-24 hours if needed to control bleeding.

For a major surgical procedure, for example, joint replacement, a single dose of 40 to 60 IU/kg of Advate should be given before surgery, and then every 8-24 hours (6-24 hours for children younger than 6) to maintain FVIII levels in the desired range until healing is complete.

The infusions can be done at a clinic or at home, but patients should not attempt to inject Advate unless they have received proper training from a doctor or other healthcare professional.

A mobile app called myPKFiT is available for use with Advate. It allows patients to track treatment, view estimated FVIII levels, and share data with their healthcare provider. Developed by Shire, now part of Takeda, myPKFiT was first CE marked in Europe in 2014 and cleared by the FDA in late 2017. The mobile app is intended for use only by people with hemophilia A who are 16 years or older and weigh at least 45 kg (about 99 pounds).

Advate in clinical trials

Advate was first approved based on the results of Phase 2/3 clinical trials testing its safety and efficacy in people who had been previously treated for hemophilia A.

Phase 2/3 clinical trials

A pivotal three-part clinical trial, called study 069901, compared Advate with Recombinate, a recombinant FVIII concentrate also marketed by Takeda. Unlike Recombinate, Advate is prepared so that it contains no human- or animal-derived proteins. The study showed that the two medications are bioequivalent, that is, they are equally absorbed by the body and work equally as well to prevent and control bleeding episodes.

The study included 111 people, 10 years or older, with moderate to severe hemophilia A. Patients received Advate for routine prophylaxis and on-demand treatment of bleeding episodes. The quality of treatment response was rated using a scale of excellent, good, fair, or none.

Among a total of 510 bleeding episodes, 473 (93%) were managed with one or two infusions of Advate and 439 (86%) were rated as excellent or good in terms of response to treatment.

Over the course of 75 days of routine prophylactic treatment, patients experienced an average of 0.52 new bleeding episodes per month (6.3 episodes per year). On average, people who did not adhere as well to routine prophylaxis experienced more bleeding episodes in a year (9.9 episodes) than those who adhered better (4.4).

All boys and men who completed the pivotal study were offered the opportunity to enter an open-label continuation study (NCT00157053). In total, 81 patients self-administered Advate on a routine prophylactic regimen for a minimum of 75 days. Results showed that the response to treatment was excellent or good for 80.4% of all bleeding episodes reported.

Another Phase 2/3 clinical trial (NCT00157105) tested the safety and efficacy of Advate for surgical use in 58 people, ages 7 to 65, with moderate to severe hemophilia A. A total of 65 surgical procedures were performed: 22 were major, 35 were minor, and eight were dental procedures.

Before surgery, patients were given Advate at a dose aimed at increasing their FVIII levels to 60% to 100% of normal (for dental procedures) or 80% to 120% of normal (for all other procedures). During surgery, Advate was given either by bolus infusion or continuous infusion. After discharge, patients continued to receive Advate for up to six weeks (for major orthopedic procedures) or up to two weeks (for all other procedures).

During surgery, bleeding control was rated as excellent or good in 61 (93.9%) of the 65 procedures; after surgery, it was rated as excellent or good in 62 (95.4%). This means that blood loss was less than expected for the type of procedure performed (excellent) or as expected for the type of procedure performed (good).

Another Phase 3 clinical trial (NCT00157157) tested the safety and efficacy of Advate in 55 children younger than 6 who had moderate to severe hemophilia A and had not been treated or had been only minimally treated with FVIII replacement therapy.

Among a total of 517 treated bleeding episodes, 463 (90%) were managed with one or two infusions of Advate, and 93% of available ratings were excellent or good in terms of response to treatment.

Phase 4 clinical trials

The approval of Advate for routine prophylaxis was based on the results of a Phase 4 clinical trial comparing the efficacy of two prophylaxis regimens against on-demand treatment in people who had been previously treated for hemophilia A.

The 18-month study (NCT00243386) included people, ages 7 to 65, with moderate to severe hemophilia A. Results showed that prophylaxis outperforms on‐demand treatment in reducing bleeding episodes.

After switching from on-demand treatment to prophylaxis, the participants experienced a reduction in the median annual bleeding rate, from 44 to one bleeding episode per patient per year. During the 12 months of prophylaxis, 22 people (33.3% overall) experienced zero bleeding episodes.

Ongoing trials

A real-world study, dubbed AHEAD (NCT02078427), is ongoing at more than 100 sites globally. It includes people of all ages with moderate to severe hemophilia who are being followed for up to 12 years in routine clinical practice.

The study’s main goal is to assess joint health in people being treated with Advate or Adynovate/Adynovi (rurioctocog alfa pegol), a recombinant FVIII concentrate based on Advate that has been modified to last longer in the blood. Other measures include annualized (joint) bleeding rate and safety.

A seven-year interim analysis included data from 711 people who were on prophylaxis or on-demand treatment with Advate. The data showed that prophylaxis outperforms on-demand treatment in reducing bleeding episodes, including those in the joints, with a greater proportion of people on prophylaxis experiencing zero bleeding episodes.

Common side effects of Advate

The most common side effects that have been reported with Advate during clinical trials are:

• fever
• headache
• cough
• the common cold
• joint pain
• vomiting
• upper respiratory tract (nose and throat) infection
• limb injury
• nasal congestion
• diarrhea.

Hypersensitivity

In taking Advate, the patient’s body may mount a hypersensitivity reaction, including anaphylaxis (severe, whole-body allergic reaction), to mouse or hamster proteins, which are present in trace amounts in the treatment. If symptoms develop, treatment with Advate should be stopped, and urgent medical attention may be required.

Symptoms of an allergic reaction include rash, itching, facial swelling, tightness of the throat, chest pain or tightness, difficulty breathing, lightheadedness, dizziness, nausea, vomiting, or fainting.

Inhibitor antibodies

The body may form inhibitor (neutralizing) antibodies against FVIII, which may stop Advate from working properly. This is common in patients who have not been previously treated (or have been only minimally treated) with replacement therapy.

If the expected levels of FVIII activity are not reached, or if bleeding does not stop with an appropriate dose, a blood test may be done to check for the presence of inhibitor antibodies and determine the amount present.

Use in pregnancy and breastfeeding

Women who are pregnant, planning to become pregnant, or breastfeeding should consult their doctor before taking Advate. It is not known if Advate is safe to use in pregnancy or if it passes into breast milk or is safe for the breastfed infant.

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