FDA Approves Baxter's ADVATE as the Only FVIII for Routine Prophylaxis

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ADVATE for routine prophylaxis reduced annual bleed events in hemophilia A patients from forty-four to one as compared to an on-demand regimen in a clinical study
Once every third day pharmacokinetic dosing option offers some patients
the opportunity for fewer infusions annually
DEERFIELD, Ill., December 16, 2011 – Baxter International Inc. today announced that the U.S. Food and Drug Administration (FDA) has approved ADVATE [Antihemophilic Factor (Recombinant) Plasma/Albumin Free Method] for routine prophylaxis to prevent or reduce the frequency of bleeding episodes in patients with hemophilia A.  ADVATE is the only antihemophilic factor approved in the United States for prophylactic use in both adults and children.
The approval is based on a Phase IV prophylaxis study sponsored by Baxter demonstrating that ADVATE for routine prophylaxis significantly reduced median annual bleed rates (ABR) in hemophilia A patients from 44 to one as compared to an on-demand regimen.  Forty-two percent of study patients experienced zero bleeds during one year on prophylaxis.  Of the two prophylactic regimens approved for use, the dosing schedule of every three days, a pharmacokinetic-driven regimen based on patient’s clinical response, offered some patients the option of fewer infusions over one year of treatment.
“Emerging data provide important information to help physicians optimize care for hemophilia patients of all ages by preventing unexpected bleeding events that can have a detrimental impact on the lives of patients,” said Leonard Valentino, M.D., Director, Rush Hemophilia and Thrombophilia Center and Section of Pediatric Hematology/Oncology, Rush University Medical Center, Chicago, and lead investigator of this study. “These data confirm the important clinical benefits of ADVATE when used as a prophylactic therapy to reduce bleeding episodes.”
The study findings demonstrated a statistically significant reduction in the median annual bleeding rate, with patients experiencing 44 bleeds (per patient per year) during on-demand treatment compared to one bleed (per patient per year) while on either of the prophylactic regimens evaluated, a 98 percent reduction in annual bleed rate (p<0.0001).  Nearly half (42 percent) of patients experienced no bleeding episodes while on one year of prophylactic treatment.  Evaluable patients had greater than or equal to 90 percent adherence to the prescribed prophylactic regimen.  While the trial was not powered to demonstrate equivalence in bleeding rate between the two prophylaxis arms, there was no statistically significant difference in bleeding frequency observed between the two prophylaxis regimens studied.
“This latest clinical milestone for ADVATE is an important step forward for people living with hemophilia A as we continue to research ways to advance care for this patient population,” said Bruce Ewenstein, M.D., Ph.D, vice president, clinical affairs, Baxter’s BioScience business. “This rigorous clinical study demonstrated that the number of bleeding episodes experienced each year could be reduced to as low as one event with prophylactic treatment.  Further, the pharmacokinetic-driven dosing regimen based on patient’s clinical response every third day, offers some patients the option of fewer infusions over one year of treatment than the current standard prophylaxis regimen.”
For the prophylaxis regimen to prevent or reduce frequency of bleeding episodes, ADVATE dosing of three to four times weekly (between 20 to 40 international units of factor VIII per kg body weight every other day) may be used.  Alternatively, an every third day dosing regimen targeted to maintain FVIII trough levels greater than or equal to one percent may be employed.  The serious adverse drug reactions (ADRs) seen with ADVATE are hypersensitivity reactions and the development of high-titer inhibitors necessitating alternative treatments to Factor VIII.  The most common ADRs observed in clinical trials (frequency ≥ 10% of patients) were pyrexia, headache, cough, nasopharyngitis, vomiting, arthralgia, limb injury.
Study Design
The approval is based on the ADVATE Phase IV study comparing two prophylactic regimens to on demand treatment of bleeding episodes in previously treated patients with severe or moderately severe hemophilia A.  The multi-center, open-label, prospective, randomized, controlled clinical trial evaluated the relative efficacy of ADVATE use in two prophylactic regimens (standard prophylaxis [20-40 international units/kg every 48 hours] and pharmacokinetic-driven prophylaxis [20-80 international units/kg every 72 hours, targeted to maintain FVIII trough levels at least 1 percent or higher]) compared to that of on-demand treatment in 53 previously treated patients with severe to moderately severe hemophilia A.  Initial treatment with six months of on-demand therapy was followed by 12 months of either prophylactic regimen.
All patients had a history of at least eight joint hemorrhages per year prior to entering the study.  Additionally, each patient evaluated was adherent to greater than 90 percent of the prescribed number of prophylactic infusions, and no patient in the study surpassed the upper boundary of 110 percent of the prescribed number of prophylactic infusions.
About ADVATE
ADVATE was initially approved by the FDA in July 2003 for control and prevention of bleeding episodes in adults and children with hemophilia A.  ADVATE (derived from the complete FVIII gene) is a recombinant FVIII therapy that is processed without any blood-based additives.  Because no blood-derived components are added at any stage of the manufacturing process, the potential risk of transmitting pathogens that may be carried in blood-based additives is eliminated.  There have been no confirmed reports of transmission of HIV, HBV or HCV with any rFVIII therapies.
ADVATE is approved in 52 countries worldwide including the United States, Canada, 27 countries in the European Union, Argentina, Australia, Brazil, Chile, Colombia, Croatia, Hong Kong, Iceland, Iraq, Japan, Macau, Malaysia, New Zealand, Norway, Puerto Rico, Serbia, Singapore, South Korea, Suriname, Switzerland, Taiwan, Uruguay and Venezuela. Since the initial approval of ADVATE eight years ago, nearly 10 billion international units have been distributed, and ADVATE is the number one chosen rFVIII worldwide.
ADVATE is an Antihemophilic Factor (Recombinant) indicated for:

• Control and prevention of bleeding episodes in adults and children (0-16 years) with Hemophilia A
• Perioperative management in adults and children (0-16 years) with hemophilia A
• Routine prophylaxis to prevent or reduce frequency of  bleeding episodes in adults and children (0-16 years) with hemophilia A
• ADVATE is not indicated for the treatment of von Willebrand disease

Detailed Important Risk Information for ADVATE
ADVATE is contraindicated in patients with known anaphylaxis to mouse or hamster protein or other constituents of the product.
Allergic-type hypersensitivity reactions, including anaphylaxis, are possible and have been reported with ADVATE.  Symptoms have manifested as dizziness, paresthesia, rash, flushing, face swelling, urticaria, dyspnea, and pruritus.  Discontinue use if hypersensitivity symptoms occur and administer appropriate emergency treatment.
Patients treated with AHF products should be monitored for the development of FVIII inhibitors.  Inhibitors have been reported following administration of ADVATE predominantly in previously untreated patients (PUPs) and previously minimally treated patients (MTPs).
If expected plasma FVIII levels are not attained, or if bleeding is not controlled with an expected dose, test for the presence of inhibitors.
The most serious adverse reactions seen with ADVATE are hypersensitivity reactions and the development of high-titer inhibitors necessitating alternative treatments to FVIII.
The most common adverse reactions observed in clinical trials (frequency less than 10% of patients) were pyrexia, headache, cough, nasopharyngitis, vomiting, arthralgia, and limb injury.
Please see full prescribing information at www.baxter.com/downloads/healthcare_professionals/products/ADVATE_PI.pdf.
About Hemophilia
Hemophilia is a rare genetic blood clotting disorder that primarily affects males.¹Â  People living with hemophilia do not have enough of, or are missing, one of the blood clotting proteins naturally found in blood.¹ Two of the most common forms of hemophilia are A and B.²  In people with hemophilia A, clotting factor VIII is not present in sufficient amounts or is absent.²Â  Without enough FVIII, people with hemophilia can experience spontaneous, uncontrolled internal bleeding that is painful, debilitating, damaging to joints and potentially fatal.²Â  People with hemophilia B (also called Christmas disease) do not have sufficient amounts of clotting factor IX.²  In about 30% of cases, there is no family history of hemophilia and the condition is the result of a spontaneous gene mutation.^3  According to the World Federation of Hemophilia, more than 400,000 people in the world have hemophilia.¹ All races and economic groups are affected equally.¹
About Baxter International Inc.
Baxter International Inc., through its subsidiaries, develops, manufactures and markets products that save and sustain the lives of people with hemophilia, immune disorders, cancer, infectious diseases, kidney disease, trauma and other chronic and acute medical conditions. As a global, diversified healthcare company, Baxter applies a unique combination of expertise in medical devices, pharmaceuticals and biotechnology to create products that advance patient care worldwide.
1. What is Hemophilia? World Federation of Hemophilia. Accessed on: 29 June 2011. Available at: http://www.wfh.org/2/1/1_1_Hemophilia.htm .
2. Frequently Asked Questions About Hemophilia. World Federation of Hemophilia. Accessed on: 29 June 2011.  Available at: http://www.wfh.org/2/1/1_1_1_FAQ.htm#difference .
3. Hemophilia A. National Hemophilia Foundation. Accessed on: 29 June 2011. Available at: http://www.hemophilia.org/NHFWeb/MainPgs/MainNHF.aspx?menuid=180&contentid=45&rptname=bleeding .