FDA Approves Baxter’s ADVATE as the Only FVIII for Routine Prophylaxis in Both Adults and Children with Hemophilia A

Press Release from BAXTER

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.¹  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.²  Without enough FVIII, people with hemophilia can experience spontaneous, uncontrolled internal bleeding that is painful, debilitating, damaging to joints and potentially fatal.²  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 .

Holiday Music to benifit vonWillibrand Disease research

Information from: Somethingelsereview.com

If you like Christmas music and want to support vWD research keep reading!!!!!!

Produced by Dan Pavelich, whose catchy confections with bands like the Bradburys and the Click Beetles have reaped rave reactions from here to eternity, Hi-Fi Christmas Party Volume 3 features a batch of the coolest holiday tunes you could hope for.

The idea for the series arrived when Dan learned his daughter, Mari, had Von Willebrand’s Disease, a bleeding disorder akin to hemophilia. He soon discovered research for the condition lacked serious funds, so he approached some of his colleagues and asked if they would submit their talents to a compilation album he was putting together where proceeds from all sales would go to research the ailment.

So not only does Hi-Fi Christmas Party (Vandalay Records) offer a great repertoire of songs, but it also benefits an awfully good cause.

As was the situation with the previous two installments of the collection, this set includes a dazzling cast of characters. Sixteen different acts total, and each one brings their own special herbs and spices to the festivities. 

For more of the reveiw, click here.

Alnylam Scientists Present New Data on RNAi Therapeutics

 

CAMBRIDGE, Mass., Dec 13, 2011 (BUSINESS WIRE) — Alnylam Pharmaceuticals, Inc., a leading RNAi therapeutics company, announced today that it presented multiple posters and presentations at the 53rd American Society of Hematology (ASH) Annual Meeting and Exposition held in San Diego, CA between December 10 — 13, 2011. At the meeting, research was presented from programs in the company’s “Alnylam 5×15” product pipeline, including pre-clinical data from ALN-APC, an RNAi therapeutic targeting protein C for the treatment of hemophilia, and ALN-HPN, an RNAi therapeutic targeting the hepcidin pathway for the treatment of refractory anemia. In addition, pre-clinical research was also presented from candidate programs in beta-thalassemia and erythropoiesis.

“The research we presented at this meeting highlights the significant progress we are making in translating RNAi therapeutics toward an innovative class of medicines for a broad range of human disease,” said Akshay Vaishnaw, M.D., Ph.D., Senior Vice President and Chief Medical Officer of Alnylam. “Specifically, we were pleased to present additional updates from some of our ‘Alnylam 5×15′ programs, including ALN-APC for the treatment of hemophilia and ALN-HPN for the treatment of refractory anemia in addition to candidate programs in beta-thalassemia and erythropoiesis. Importantly, all four programs are focused on genetically defined targets expressed in the liver, where we have recently proven safe and effective delivery in man, with target and/or disease biomarkers measureable in early clinical studies. We remain on track to nominate our fifth ‘Alnylam 5×15′ program at or around year’s end from these and other candidate programs.”

Presentations and posters from Alnylam scientists at the ASH Meeting included a poster titled “RNAi-Mediated Inhibition of Activated Protein C. A New Approach for Hemophilia Treatment,” where Alnylam scientists presented pre-clinical data from its ALN-APC program. These data demonstrate dose-dependent silencing of protein C mRNA with silencing of greater than 90% and an ED50 of approximately 0.02 mg/kg. When administered as a single dose of 0.3 mg/kg, the lipid nanoparticle (LNP)-formulated siRNA achieved greater than 75% silencing of protein C mRNA with effects lasting for over two weeks. Based on Western blot analysis, the reduction of protein C mRNA led to virtually undetectable levels of circulating protein C protein levels in plasma. By reducing levels of protein C, ALN-APC is expected to increase thrombin generation in hemophilia.

A presentation titled “Targeting the Hepcidin Pathway with RNAi Therapeutics for the Treatment of Anemia,” showed new pre-clinical data from the company’s ALN-HPN program for the treatment of refractory anemia. New data was shown highlighting the ability of an RNAi therapeutic to silence the hepcidin pathway in pre-clinical models, resulting in associated dose-dependent increases in serum iron and transferrin saturation, a measure of effective iron mobilization in vivo. New data also revealed transferrin receptor type 2 (TFR2) as the optimal target in the hepcidin pathway, as TFR2 silencing was associated with marked decreases in hepcidin expression and greater levels of transferrin saturation as compared with direct targeting of the hepcidin mRNA itself. TFR2 silencing was also found to be more effective than direct silencing of hepcidin in animal models, including correction of hemoglobin levels in a model of inflammatory anemia. TFR2 is a genetically validated target as loss of function human mutations are associated with a hereditary form of hemochromatosis. Further efforts on ALN-HPN will focus on TFR2 as the molecular target.

In a poster titled “RNAi-Mediated Inhibition of Tmprss6 Elevates Hamp1 [Hepcidin] Expression and Reduces Serum Iron Levels in Mice,” Alnylam scientists and collaborators from Children’s Hospital Boston showed that the systemic administration of an LNP-formulated siRNA targeting Transmembrane protease, serine 6 (Tmprss6) represents a potential novel approach to treat congenital iron overload disorders. In a pre-clinical model of iron overload in beta-thalassemia, potent and dose dependent silencing of Tmprss6 was achieved, resulting in a concomitant induction of hepcidin mRNA. As a result of increased hepcidin levels, treatment with the Tmprss6 siRNA resulted in significant decreases in serum iron concentration and transferrin saturation. Moreover, Tmprss6 silencing with a single dose of the RNAi therapeutic was associated with a dramatic normalization of multiple hematological parameters including hemoglobin, normalization of splenic iron levels and tissue histology, and reductions in splenomegaly. These findings suggest that iron restriction via Tmprss6 silencing can correct the disease phenotype of beta-thalassemia intermedia in a pre-clinical model.

Lastly, in a poster titled “Liver Specific Delivery of siRNA Targeting EGLN Prolyl Hydroxylases Activates Hepatic Erythropoietin Production and Stimulates Erythropoiesis,” Alnylam scientists and collaborators at the Dana-Farber Cancer Institute and the Massachusetts Institute of Technology (MIT) highlighted the potential of RNAi therapeutics targeting liver-expressed egl nine homolog (EGLN) prolyl hydroxlase genes to promote effective and durable erythropoiesis. Pre-clinical data demonstrated that LNP-formulated EGLN siRNA induced hepatic erythropoietin (EPO) mRNA activation leading to increased serum EPO levels and stimulation of erythropoiesis. Following a single dose, increases in serum EPO and hematocrit were durable for approximately two weeks and one month, respectively. Treatment with EGLN siRNAs corrected anemia in both renal failure and inflammatory anemia pre-clinical disease models.

About RNA Interference (RNAi)

RNAi (RNA interference) is a revolution in biology, representing a breakthrough in understanding how genes are turned on and off in cells, and a completely new approach to drug discovery and development. Its discovery has been heralded as “a major scientific breakthrough that happens once every decade or so,” and represents one of the most promising and rapidly advancing frontiers in biology and drug discovery today which was awarded the 2006 Nobel Prize for Physiology or Medicine. RNAi is a natural process of gene silencing that occurs in organisms ranging from plants to mammals. By harnessing the natural biological process of RNAi occurring in our cells, the creation of a major new class of medicines, known as RNAi therapeutics, is on the horizon. Small interfering RNAs (siRNAs), the molecules that mediate RNAi and comprise Alnylam’s RNAi therapeutic platform, target the cause of diseases by potently silencing specific mRNAs, thereby preventing disease-causing proteins from being made. RNAi therapeutics have the potential to treat disease and help patients in a fundamentally new way.

About Alnylam Pharmaceuticals

Alnylam is a biopharmaceutical company developing novel therapeutics based on RNA interference, or RNAi. The company is leading the translation of RNAi as a new class of innovative medicines with a core focus on RNAi therapeutics for the treatment of genetically defined diseases, including ALN-TTR for the treatment of transthyretin-mediated amyloidosis (ATTR), ALN-PCS for the treatment of severe hypercholesterolemia, ALN-HPN for the treatment of refractory anemia, and ALN-APC for the treatment of hemophilia. As part of its “Alnylam 5×15(TM)” strategy, the company expects to have five RNAi therapeutic products for genetically defined diseases in advanced stages of clinical development by the end of 2015. Alnylam has additional partner-based programs in clinical or development stages, including ALN-RSV01 for the treatment of respiratory syncytial virus (RSV) infection, ALN-VSP for the treatment of liver cancers, and ALN-HTT for the treatment of Huntington’s disease. The company’s leadership position on RNAi therapeutics and intellectual property have enabled it to form major alliances with leading companies including Merck, Medtronic, Novartis, Biogen Idec, Roche, Takeda, Kyowa Hakko Kirin, and Cubist. In addition, Alnylam and Isis co-founded Regulus Therapeutics Inc., a company focused on discovery, development, and commercialization of microRNA therapeutics; Regulus has formed partnerships with GlaxoSmithKline and Sanofi. Alnylam has also formed Alnylam Biotherapeutics, a division of the company focused on the development of RNAi technologies for application in biologics manufacturing, including recombinant proteins and monoclonal antibodies. Alnylam’s VaxiRNA(TM) platform applies RNAi technology to improve the manufacturing processes for vaccines; GlaxoSmithKline is a collaborator in this effort. Alnylam scientists and collaborators have published their research on RNAi therapeutics in over 100 peer-reviewed papers, including many in the world’s top scientific journals such as Nature, Nature Medicine, Nature Biotechnology, and Cell. Founded in 2002, Alnylam maintains headquarters in Cambridge, Massachusetts. For more information, please visit www.alnylam.com .

Alnylam Forward-Looking Statements

Various statements in this release concerning Alnylam’s future expectations, plans and prospects, including without limitation, statements regarding Alnylam’s views with respect to the potential for RNAi therapeutics, including ALN-APC and ALN-HPN, its expectations regarding the potential of identifying RNAi therapeutics for beta-thalassemia and erythropoiesis, its expectations with respect to the timing and success of its pre-clinical studies, the expected timing for nominating the fifth ‘Alnylam 5×15′ program, and Alnylam’s expectations regarding its “Alnylam 5×15″ product strategy, constitute forward-looking statements for the purposes of the safe harbor provisions under The Private Securities Litigation Reform Act of 1995. Actual results may differ materially from those indicated by these forward-looking statements as a result of various important factors, including, without limitation, Alnylam’s ability to discover and develop novel drug candidates, successfully demonstrate the efficacy and safety of its drug candidates, including ALN-APC, ALN-HPN, and potential candidates for beta-thalassemia and erythropoiesis , the pre-clinical and clinical results for its product candidates, which may not support further development of product candidates, actions of regulatory agencies, which may affect the initiation, timing and progress of clinical trials, obtaining, maintaining and protecting intellectual property, obtaining regulatory approval for products, competition from others using technology similar to Alnylam’s and others developing products for similar uses, and Alnylam’s ability to establish and maintain strategic business alliances and new business initiatives, as well as those risks more fully discussed in the “Risk Factors” section of its most recent quarterly report on Form 10-Q on file with the Securities and Exchange Commission. In addition, any forward-looking statements represent Alnylam’s views only as of today and should not be relied upon as representing its views as of any subsequent date. Alnylam does not assume any obligation to update any forward-looking statements.

SOURCE: Alnylam Pharmaceuticals, Inc.

        
        Alnylam Pharmaceuticals, Inc. 
        Cynthia Clayton, 617-551-8207
        Senior Director, Investor Relations and 
        Corporate Communications 
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        (Media) 
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Gene therapy proves effective for hemophilia B

SAN DIEGO | Sat Dec 10, 2011 3:42pm EST By Deena Beasley

(Reuters) – A single treatment with gene therapy, an experimental technique for fixing faulty genes, has been shown for the first time to boost output of a vital blood clotting factor, possibly offering a long-term solution for people with hemophilia B.

Researchers said the same technology was also being studied as a treatment for hemophilia A, the far more common type of the inherited bleeding disorder.

“It is a technique for potentially permanently curing patients,” said Dr. Charles Abrams, American Society of Hematology secretary and associate chief of hematology/oncology at the University of Pennsylvania in Philadelphia.

The strategy involves replacing the defective gene that causes the bleeding disorder with a correct version delivered via a virus to the patient’s liver cells — the only cells in the body capable of producing certain clotting factors missing or deficient in people with hemophilia.

The factors are numbered using Roman numerals. The two main forms of the disease are hemophilia A, caused by a lack of clotting factor VIII, and hemophilia B, caused by a lack of clotting factor IX.

Researchers from the University College London Cancer Institute and St. Jude Children’s Research Hospital in Memphis, Tennessee, studied six men with severe hemophilia B who were producing clotting factor IX, also called FIX, at less than 1 percent of normal levels. The general goal of current treatment with manufactured FIX is to achieve factor levels greater than 1 percent of normal.

Four of the six trial participants have stopped routine treatment and remain free of spontaneous bleeding. The other two have increased the interval between FIX infusions to once every 10 days to two weeks from two to three times a week, said Dr. Andrew Davidoff, chairman of the department of surgery at St. Jude’s and co-author of the study.

HIGH COST FOR CURRENT TREATMENT

Frequent treatments with manufactured FIX can cost hundreds of thousands of dollars a year, making hemophilia a tempting target for gene therapy.

The trial “is truly a landmark study,” Dr. Katherine Ponder, hematology and oncology professor at Washington University in St. Louis, said in a New England Journal of Medicine editorial.

“If further studies determine that this approach is safe, it may replace the cumbersome and expensive protein therapy currently used for patients with hemophilia B,” she wrote.

The trial results were published in the NEJM and reported on Saturday at a meeting of the American Society of Hematology in San Diego.

The approach involved the use of a novel viral “vector,” designed to target the liver specifically.

The six trial subjects were broken into three groups with each group receiving a different concentration of new genes.

FIX levels in the first subject have remained at 2 percent for nearly two years, while the two patients treated with the highest dose have seen FIX levels rise to between 3 and 12 percent, researchers said.

One high-dose subject developed elevated levels of transaminases, an indicator of possible liver damage, and another had a slight increase in liver enzymes. Both cases were resolved with steroids, the researchers said.

Plans are to treat more patients with the highest dose used so far, and if research continues to succeed, the treatment could be widely available “in the next five years or so,” said Dr. Amit Nathwani, co-lead study author of the Department of Hematology at UCL Cancer Institute in London.

He also said the team was working to use the technique for treating hemophilia A.

ISI Group analyst Mark Schoenebaum said the gene therapy could pose big competition for companies such as Biogen Idec that are producing recombinant factor concentrates.

“This clearly presents a curveball to our (and much of Wall Street’s) assumptions around the future of the hemophilia market,” he said in an email to investors.

The analyst said estimated sales of the hemophilia factors accounted for between $10 and $17 of his $125 price target for shares of Biogen, which closed at $112.95 on Friday.

People with hemophilia bleed more following trauma than people without the disease, and those with severe disease may bleed spontaneously.

Hemophilia B is much less common than hemophilia A. About one in five hemophilia patients has hemophilia B, according to the National Institutes of Health.

The global market for Factor VIII products is about $5 billion, while the market for Factor IX is worth about $1 billion.

Hemophilia is an inherited condition that affects men more frequently. Worldwide, about one in 5,000 men is born with hemophilia A and 1 in 25,000 men is born with hemophilia B each year.

(Reporting by Deena Beasley)

BloodCenter of Wisconsin Announces Three New Assays for von Willebrand Disease

Posted on: November 27, 2011 @ ADVANCE

For nearly 30 years, the Hemostasis Laboratory, part of Diagnostic Laboratories at BloodCenter of Wisconsin, has built a reputation for detail and quality in its evaluations. Hemostasis Reference Laboratory at BloodCenter of Wisconsin is proud to offer the most comprehensive von Willebrand Disease testing in the United States. Now, BloodCenter is pleased to announce three new assays to add to the largest menu of assays: von Willebrand Factor (VWF) Quantitative Multimer, VWF D1472H Ristocetin-binding Polymorphism and VWF Full Gene Sequencing.

VWF Quantitative Multimer is the first offering in the market. By taking a historically subjective analysis and making it quantitative, BloodCenter has increased diagnostic confidence in the result. Doctors will have quantitative information on the severity of the multimer abnormality. Quantitation also acts as a new research tool for evaluation of patients with acquired defects of VWF such as people with heart disease being treated with a ventricular assist device.

VWF D1472H Ristocetin-binding Polymorphism affects the most commonly used test to evaluate VWF function — the VWF:RCo test. The D1472H variation of the VWF gene appears to interfere with this test, resulting in an inaccurate measure of VWF function. This genetic variation is carried by 63 percent of african Americans and 17 percent of caucasian Americans, and its significance was identified at BloodCenter’s Blood Research Institute by Veronica Flood, M.D. and Robert R. Montgomery, M.D. The D1472H test allows identification of these people promoting accurate patient diagnosis.

VWF Full Gene Sequencing adds to our current strength in genetic diagnosis of von Willebrand disease. Patients with a quantitative deficiency of VWF are at increased risk for bleeding. Many of these patients have low VWF levels due to defects of their VWF gene.

New Assays for von Willebrand Disease VWF gene sequence analysis expands the ability of physicians to diagnose their patients and improves the ability of patients to understand their disease and make family planning decisions. Many of the patient samples received at BloodCenter are for evaluation of inherited and acquired bleeding disorders. Correctly diagnosing von Willebrand Disease is complex but essential to providing optimal treatment.

BloodCenter of Wisconsin is actively involved in von Willebrand Disease research and one of the BloodCenter’s goals is to refine the diagnostic process by contributing sophisticated analytic methods and developing evidence-based treatment protocols.

The experience of our Diagnostic Laboratories team, and the desire to provide industry-leading service, enables BloodCenter to go beyond simply providing a test result. The Hemostasis Reference Laboratory’s Medical Director, Dr. Kenneth D. Friedman, M.D. stated, “These tests have the capacity to allow hematologists to take better care of their patients with von Willebrand Disease.”

Strong History of Innovation, Expertise and Results BloodCenter’s Hemostasis Reference Laboratory has an international reputation for its diagnostic services, scientific excellence, physician consultation and innovative approaches. Since its inception in 1981, the Hemostasis Reference Laboratory continues to provide comprehensive diagnostic testing for bleeding, thrombotic, fibrinolytic and platelet function disorders.

BloodCenter is unique as they have a large team of experts who are interested in advancing both the understanding and care of patients with von Willebrand Disease.  Team members include Thomas Abshire, MD; Veronica Flood, MD; Kenneth Friedman, MD; Joan Gill, MD; Sandy Haberichter, PhD and Robert Montgomery, MD.   “It is very rewarding to see a basic and clinical research finding translated into new clinically relevant testing that offers patients the opportunity for improved clinical care,” Dr. Montgomery indicated.

For more than 50 years, BloodCenter has helped clinicians serve patients with blood disorders. The Diagnostic Laboratories staff is dedicated to improving patient care through their leadership

Inspiration Biopharmaceuticals Initiates Second Pivotal Clinical Study of Innovative Hemophilia Therapy OBI-1

 From Inspiration Bio

Laguna Niguel, CA, November 28, 2011 – Inspiration Biopharmaceuticals, Inc. (Inspiration) today announced the initiation of patient enrollment in the second of two pivotal studies in the Company’s OBI-1 Accur8 clinical trial program. In the newly initiated clinical study, OBI-1, an intravenous recombinant porcine factor VIII (FVIII) product, will be evaluated for the treatment of individuals with congenital hemophilia A who have developed inhibitory antibodies (inhibitors) against their human FVIII replacement therapy. In achieving this milestone, Inspiration has received a $25 million milestone payment from the Ipsen Group (Euronext: IPN; ADR: IPSEY), under a partnership agreement signed with Ipsen in January 2010. In return, Inspiration has issued Ipsen a convertible note, bringing Ipsen’s fully diluted ownership position in Inspiration to 40.7%.

The OBI-1 pivotal clinical study is a prospective, non-randomized, open-label study evaluating the efficacy of OBI-1 for the treatment of serious bleeding episodes, including episodes that are a threat to a patient’s life or vital organs.

 Dr. Johnny Mahlangu, MD, Director of the Adult Hemophilia Comprehensive Care Unit at Johannesburg Hospital, and President of the South African Society of Hematology, commented, “There remains a significant unmet medical need when it comes to treating individuals with hemophilia A who have developed inhibitors. Current therapies do not reach the same level of efficacy as replacement therapy for non-inhibitor patients, leading to potential joint complications, increased risk of bleeding, pain and impact on the patient’s quality of life. Unlike available bypassing agents, OBI-1 facilitates the intrinsic hemostatic pathway, and therefore may allow clinicians to correlate activity and efficacy with FVIII levels (a surrogate for efficacy), enabling them to guide dosing and better predict treatment outcomes. We are pleased to have enrolled the first patient in this pivotal clinical study.”

Inspiration in-licensed OBI-1 from Ipsen as part of their January 2010 partnership agreement, whereby Inspiration is responsible for the clinical development, regulatory approval and commercialization of the product. Previously, in November 2010, Inspiration initiated the first pivotal study of OBI-1 for the treatment of individuals with acquired hemophilia A, a rare, potentially life-threatening autoimmune bleeding disorder caused by the development of inhibitors against endogenous FVIII. Results from the first patients in this clinical study were presented in a Scientific Session held in conjunction with the 23rd Congress of the International Society on Thrombosis and Haemostasis (ISTH) in July 2011. Enrollment in the OBI-1 acquired hemophilia clinical trial is ongoing.

John P. Butler, Chief Executive Officer of Inspiration, commented, “Inspiration is committed exclusively to driving innovation that can bring positive impact to the treatment of people with hemophilia. We now have OBI-1 in pivotal development for multiple indications. We also recently announced the filing of a Marketing Authorization Application (MAA) for our other lead program, IB1001, a recombinant factor IX product for the treatment of hemophilia B. These two late stage products, along with our preclinical programs for factor VIIa and FVIII deficiency, gives Inspiration one of the broadest pipelines for hemophilia treatment in the industry. As a company, we are committed to developing and commercializing an array of hemophilia products, which will provide value to physicians and to people living with the condition worldwide.”

About Hemophilia

Hemophilia is a bleeding disorder caused by low levels or the absence of a protein called a coagulation factor, essential for blood clotting. The two most common forms of hemophilia are types A and B. Hemophilia A is caused by a factor VIII deficiency and the congenital form occurs in ~1 out of every 5,000 male births. Hemophilia B is caused by factor IX deficiency and occurs in ~1 out of every 30,000 male births. Approximately 60% of persons with hemophilia have a severe condition, which results in frequent spontaneous bleeding episodes, in addition to serious bleeding after injuries. The annual market for hemophilia treatments is estimated at $8 billion worldwide.

Approximately one-third of individuals with hemophilia A develop an immune reaction (inhibitors) to human FVIII, and can no longer respond to replacement treatment with the coagulation factor. Current therapies, specifically human factor VIIa (NovoSeven®) and FEIBA, work by bypassing the natural hemostatic pathway.

About OBI-1

OBI-1, a recombinant form of porcine FVIII which may possess low cross reactivity to antihuman FVIII antibodies, is a replacement therapy, facilitating the intrinsic hemostatic pathway. This should allow clinicians to correlate activity and efficacy with FVIII levels, a surrogate for efficacy in hemophilia, and therefore guide dosing to better monitor and predict treatment outcomes. OBI-1 presents a unique and alternative approach to address the needs of individuals who have developed inhibitors to FVIII and is highly desired by the medical community.

For more information about enrolling in one of Inspiration’s clinical trials, please visit www.hemophiliaregistry.com or call 1-800-361-3227. For more information on the ongoing clinical studies, please visit http://www.clinicaltrials.gov.

About Inspiration Biopharmaceuticals

Inspiration Biopharmaceuticals is dedicated exclusively to developing treatments for hemophilia, with a primary mission to broaden access to care, including prophylactic therapy, and to improve the treatment of individuals with inhibitor complications. Inspiration has a broad portfolio of recombinant hemophilia products, which includes two products in late-stage clinical development and two preclinical programs.

Inspiration’s two lead programs are IB1001, an intravenous recombinant factor IX (FIX) product being developed for the treatment and prevention of bleeding in individuals with hemophilia B, and OBI-1, an intravenous recombinant porcine factor VIII (FVIII) product being developed for the treatment of individuals with congenital hemophilia A who have inhibitors against human FVIII and for individuals with acquired hemophilia A. Inspiration recently submitted its first marketing application for IB1001 in Europe, with a subsequent regulatory filing planned in the U.S in the first half of 2012. Earlier-stage preclinical programs at Inspiration are focused on human recombinant factor VIIa (FVIIa), for individuals with either hemophilia A or hemophilia B who have developed inhibitors, and for individuals with factor VII deficiency; and human recombinant FVIII, to treat individuals with hemophilia A.

Inspiration has extensive expertise and experience in hemophilia product development, biologics manufacturing, regulatory approval and global commercialization. The Company’s senior leadership was directly responsible for the development and commercialization of the majority of hemophilia products currently on the market.

In addition, in January 2010, Inspiration entered into a strategic partnership with the Ipsen Group (EURONEXT: IPN; ADR: IPSEY), leveraging the combined expertise and resources of the two companies, to develop a broad portfolio of hemophilia products. As announced in late August 2011, Ipsen and Inspiration extended their partnership to create a hemophilia business unit structure that will act as the exclusive sales organization for all hemophilia products commercialized under the Inspiration brand inEurope. For further information on Inspiration, please visit http://www.inspirationbio.com.

Contacts:

Company
Gordon H. Busenbark
Senior Vice President, Chief Financial Officer
Email: gbusenbark@inspirationbio.com

Media
Justin Jackson
Michelle Szwarcberg
Burns McClellan
Tel: +1-212-213-0006
Email: jjackson@burnsmc.com
mszwarcberg@burnsmc.com

Tulane researcher finds treatment for hemophilia

DEERFIELD, ILL., November 2, 2011 – Results from an investigator-initiated study, which evaluated whether prophylactic use of FEIBA [Anti-inhibitor Coagulant Complex] can achieve a decrease in the frequency of joint and other bleeding events in patients with severe hemophilia A and inhibitors compared to on-demand therapy, were published today in The New England Journal of Medicine.  Patients with severe hemophilia A and inhibitors are at increased risk for serious bleeding complications.  Effective strategies to prevent bleeding in inhibitor patients have not yet been established.  Prophylaxis, where approved, is used to prevent a bleed and on-demand treatment is used only at the time of a bleeding episode.

“The single greatest remaining challenge in the management of hemophilia is the development of inhibitors, often occurring in young patients, that can lead to more difficult to control and sometimes life-threatening bleeding,” said Bruce Ewenstein, M.D., Ph.D., vice president, clinical affairs in Baxter’s BioScience business.  “The Pro-FEIBA investigator-initiated study is the first randomized prospective, controlled clinical trial to evaluate the ability of FEIBA prophylaxis to reduce bleeding events, which is particularly encouraging given that there are limited treatment options available for these patients.”

The Prophylaxis with Factor Eight Inhibitor Bypassing Activity (Pro-FEIBA) study reported that patients with severe hemophilia A treated with FEIBA prophylactically during a six-month period experienced a 62 percent reduction in all bleeds in the prophylaxis period, an average of 5 bleeding events compared to an average of 13.1 during the on-demand treatment period.  Sixty two percent of patients (16 of 26) were in the group that responded well to prophylaxis treatment, defined as those who had a greater than or equal to 50 percent reduction in overall bleeding, the target for success defined in the study protocol.  In this “good responder group,” the overall reduction in bleeding rate was 84 percent.  Thirty eight percent of patients (10 of 26) had a less than 50 percent reduction in bleeding events during the prophylactic period.  In this group, bleeding was reduced by 28 percent.  Two patients had an increase in bleeding events in the prophylaxis period.

Secondary outcome measurements were joint bleeding and target joint bleeding.  During the prophylaxis period, patients experienced a 61 percent reduction in joint bleeding, an average of 4.2 joint bleeds versus an average of 10.8 during the on-demand treatment period.  In target joints (those most prone to frequent bleeding, such as the elbow, knee and ankle), patients experienced a 72 percent reduction in bleeding.  The number of patients with bleeding in target joints decreased from 18 to 11. Of those patients in the study achieving a reduction in bleeds, all were achieved with three doses of FEIBA (85 U/kg ± 15 percent) per week.

One adverse event related to the study drug was an allergic reaction.  Three patients (9 percent) had multiple events related to central venous access devices, including infection, bleeding, and line placement and removal.

A limitation of the study was its relatively short duration.  While joint and other bleeding episodes were reduced during the six-month prophylaxis period, a longer, larger, parallel design trial is needed to determine if regular FEIBA infusions are a safe and effective treatment option for hemophilia A patients with inhibitors.  In addition, the authors state it is not possible to draw conclusions regarding relationships between patient age and the benefits of prophylaxis.  A Baxter-sponsored clinical study, FEIBA PROOF, is evaluating the efficacy and safety of FEIBA prophylaxis compared to on-demand treatment in those living with hemophilia with high-titer inhibitors. 

The Pro-FEIBA study was conducted by lead investigators Cindy Leissinger, M.D., from the Louisiana Center for Bleeding and Clotting Disorders, Tulane University Medical Center, New Orleans, USA, and Alessandro Gringeri, M.D., from the Department of Medicine and Medical Specialties, Fondazione IRCCS Cà Granda, Ospedale Maggiore Policlinico and Università degli Studi di Milano, Milan, Italy.  The lead investigators oversaw all aspects of the study including design, data collection and analysis and manuscript development and submission.  Baxter supplied the study drug (FEIBA) and provided a financial grant to support the study and authoring of the manuscript.  The manuscript was subsequently revised by the authors who assumed responsibility for its accuracy and completeness.

About the Study Design
The objective of the investigator-initiated Pro-FEIBA study was to test if prophylaxis with FEIBA over a six-month period may be safe and effective in preventing joint and other bleeds in severe hemophilia A patients with inhibitors compared to on-demand treatment.  Following the initial six-month study period (with 12 patients receiving on-demand therapy and 14 receiving prophylaxis), each group crossed-over to the alternate treatment period for six months after a three-month wash-out period.  The crossover design produced valid results with fewer patients than required for a parallel study design¹.  Thirty-four patients were enrolled in the study, with 26 patients evaluated in the final analysis.

About Hemophilia (A & B) and Inhibitors
Hemophilia is a rare genetic blood clotting disorder that primarily affects males. People living with hemophilia do not have enough of, or are missing, one of the blood clotting proteins naturally found in blood.  In people with hemophilia A, clotting factor VIII is not present in sufficient amounts or is absent.  People with hemophilia do not bleed more profusely or faster than normal but bleed for a longer period of time. 

Hemophilia is usually inherited, and about one in every 5,000 males is born with the disorder.  About one third of new cases are caused by a new mutation of the gene in the mother or the child.  In these cases, there is no previous history of hemophilia in the family. According to the World Federation of Hemophilia, more than 400,000 people in the world have hemophilia.  All races and economic groups are affected equally.

Inhibitor development is considered one of the most serious adverse reactions associated with hemophilia treatment.  Studies suggest this may occur in three out of every 10 people with severe hemophilia A and one out of every 20 people with hemophilia B. Inhibitors are antibodies that people with hemophilia can generate following exposure to blood clotting factor replacement therapy.  These antibodies neutralize (inhibit) the action of clotting factor, which increases the risk of bleeding in people with inhibitors. Hemophilia patients with inhibitors have an increased risk of uncontrolled bleeding and bleeds are much more difficult to control compared to patients without inhibitors.  Consequently, these patients can develop complications such as increased need for surgery and increased complexity of surgery. 

The information in this statement is intended for scientific exchange only and is not intended for any other purpose.

About FEIBA
FEIBA is not indicated for prophylaxis use in the United States.  Canada, Italy, The Netherlands, Israel, Australia/New Zealand, Japan, South Korea, and Taiwan also do not have a prophylaxis indication.

Indications
In the US, FEIBA NF [Anti-Inhibitor Coagulant Complex] is indicated for the control of spontaneous bleeding episodes or to cover surgical interventions in hemophilia A and hemophilia B patients with inhibitors.

Clinical experience suggests that patients with a Factor VIII inhibitor titer of less than 5 B.U. may be successfully treated with Antihemophilic Factor.

Patients with titers ranging between 5 and 10 B.U. may either be treated with Antihemophilic Factor or FEIBA NF. Cases with Factor VIII inhibitor titers greater than 10 B.U. have generally been refractory to treatment with Antihemophilic Factor.

Detailed Risk Information About FEIBA NF
Thrombotic and thromboembolic events have been reported during postmarketing surveillance following infusion of FEIBA VH or FEIBA NF, particularly following the administration of high doses and/or in patients with thrombotic risk factors.

The use of FEIBA NF is contraindicated:

• In patients who have known anaphylactic or severe hypersensitivity reactions to the product
• In patients who are known to have a normal coagulation mechanism
• For the treatment of bleeding episodes resulting from coagulation factor deficiencies in the absence of inhibitors to coagulation factor VIII or coagulation factor IX
• In patients with significant signs of disseminated intravascular coagulation (DIC)
• In patients with acute thrombosis or embolism (including myocardial infarction)

At first sign or symptoms of an infusion/hypersensitivity reaction or a thrombotic/thromboembolic event, FEIBA NF administration should be stopped immediately and diagnostic and therapeutic measures initiated as appropriate.

Allergic-type hypersensitivity reactions, including severe anaphylactoid reactions, have been reported following the infusion of FEIBA. The symptoms include urticaria, angioedema, gastrointestinal manifestations, bronchospasm, and hypotension; these reactions can be severe and can be systemic.

Many of the reported cases of thromboembolic events occurred with doses above 200 units/kg/day or in patients with other risk factors.

Infusion of FEIBA NF should not exceed single dosage of 100 U/kg and daily doses of 200 U/kg of body weight. Patients receiving more than 100 U/kg of FEIBA NF must be monitored for the development of DIC and/or symptoms of acute coronary ischemia. High doses of FEIBA NF should be given only as long as absolutely necessary to stop bleeding.

FEIBA VH or FEIBA NF should be used with particular caution and only if there are no therapeutic alternatives in patients at risk of DIC, arterial or venous thrombosis.

If clinical signs of intravascular coagulation occur, which include changes in blood pressure, changes in pulse rate, respiratory distress, chest pain and/or cough, infusion of FEIBA NF should be stopped promptly.

Non-hemophilic patients with acquired inhibitors against factors VIII, IX or XII may have both a bleeding tendency and an increased risk of thrombosis at the same time.

FEIBA NF is made from human plasma. It may carry a risk of transmitting infectious agents, e.g., viruses and theoretically, the Creutzfeldt-Jakob disease (CJD) prion.

Adverse reactions reported in clinical studies with FEIBA were anamnestic response, somnolence, dizziness, dysgeusia, dyspnea, hypoesthesia, nausea, chills, pyrexia, chest pain and chest discomfort.

For information on FEIBA use in the United States, please visit:
http://www.baxter.com/healthcare_professionals/products/feiba_nf.html

Licenses and licensing conditions may vary from country to country; therefore please always consult your local full prescribing information. Please check FEIBA website for information on indications approved in other countries.

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, 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.

Baxter and Feiba are registered trademarks of Baxter International Inc., its subsidiaries or affiliates.

1. Louis TA, Lavori PW, Bailar JC, 3rd, Polansky M. Crossover and self-controlled designs in clinical research. N Engl J Med 1984;310:24-31.

Originally from Baxter website.