U.S. FDA Accepts for Review CSL Behring’s Biologics License Application for Its Novel rVIII-SingleChain Therapy for Patients with Hemophilia A

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rVIII-SingleChain underscores CSL Behring’s deep commitment to developing and delivering specialty biotherapies that improve the well-being of patients with serious diseases

KING OF PRUSSIA, Pa. — 28 July 2015

CSL Behring announced today that the U.S. Food and Drug Administration has accepted for review the company’s Biologics License Application (BLA) for its novel investigational recombinant factor VIII single-chain (rVIII-SingleChain) for the treatment of hemophilia A. In the pivotal clinical trial, rVIII-SingleChain met all primary endpoints.

Hemophilia A is a congenital bleeding disorder characterized by deficient or defective factor VIII; nearly all affected patients are male. People with hemophilia A may experience prolonged or spontaneous bleeding, especially into the muscles, joints, or internal organs. The condition affects approximately 1 in 6,000 male births.

“CSL Behring has one of the industry’s largest portfolios of biotherapies that improve the care and well-being of patients with a bleeding disorder,” said Dr. Andrew Cuthbertson, Chief Scientific Officer and Director of R&D, CSL Limited. “Our scientific expertise and relationship with the bleeding disorders community led us to seek further advancements in the care and treatment of hemophilia. Today, we have the only recombinant single-chain factor VIII product in late-stage development for the management of hemophilia A, and we are excited to be one step closer to providing this innovative treatment to patients in the U.S.”

The BLA submission is based on the AFFINITY clinical development program, which includes a phase I/III open-label, multi-center trial examining safety and efficacy. The pharmacokinetics of rVIII-SingleChain compared with recombinant human antihemophilic factor VIII (octocog alfa) was also studied. Study design details for rVIII-SingleChain are available at clinicaltrials.gov.

Results from the phase I/III study were recently presented at the International Society on Thrombosis and Haemostasis (ISTH) congress in Toronto. Patients treating prophylactically had a median annualized bleeding rate (ABR) of 1.14 and a median annualized spontaneous bleeding rate (AsBR) of 0.00. The data also showed that, of 848 bleeds treated in the study, 94 percent were controlled with no more than two infusions of rVIII-SingleChain, with 81 percent controlled by one infusion. Moreover, hemostatic control of a bleeding event treated with rVIII-SingleChain was assessed by the investigator as excellent or good 94 percent of the time (835 assessed bleeding events).

The results presented included data on more than 14,000 exposure days in 146 patients on prophylaxis and 27 patients treating on demand for a bleeding event. In total, 120 patients were treated for more than 50 days of exposure; 52 had more than 100 days of exposure. In the prophylaxis group, 32 percent of patients were dosed twice weekly and 54 percent received treatment three times per week; the regimen was determined by the investigator. The most common adverse events were naso-pharyngitis, arthralgia, and headache. No inhibitors were reported.

About rVIII-SingleChain

Specifically designed for greater molecular stability, rVIII-SingleChain is the first and only single-chain factor VIII (FVIII) product in late-stage development for the treatment of hemophilia A. rVIII-SingleChain (also known as CSL627) has a strong affinity for von Willebrand factor, leading to greater stability and integrity of FVIII in circulation. For more information about CSL Behring’s recombinant products in development to treat hemophilia, visit http://www.cslbehring.com/products/bleeding-disorders/novel-recombinant-hemophilia-treatments.

About CSL Behring

The people and science of CSL Behring save lives around the world. We develop and deliver innovative specialty biotherapies, driven by our 100-year promise to help people with life-threatening conditions live full lives. With 14,000 employees and operations in 30 countries, CSL applies world-class R&D, high-quality manufacturing and patient-centered management.

CSL Behring therapies are used around the world to treat coagulation disorders including hemophilia and von Willebrand disease, primary immune deficiencies, hereditary angioedema and inherited respiratory disease, and neurological disorders in certain markets. The company’s products are also used in cardiac surgery, organ transplantation, burn treatment and to prevent hemolytic disease of the newborn.

CSL Behring operates one of the world’s largest plasma collection networks, CSL Plasma. CSL Behring is a global biopharmaceutical company and a member of the CSL Group of companies. The parent company, CSL Limited (ASX:CSL), is headquartered in Melbourne, Australia. For more information, visit www.cslbehring.com.

For original article click here.

CSL Behring Submits Biologics License Application for FDA Approval of Recombinant Fusion Protein Linking Coagulation Factor IX with Recombinant Albumin (rIX-FP) for Hemophilia B Patients

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KING OF PRUSSIA, Pa. — 16 December 2014

CSL Behring announced today it has submitted a biologics license application (BLA) to the United States Food and Drug Administration (FDA) for the marketing authorization of its long-acting fusion protein linking recombinant coagulation factor IX with recombinant albumin (rIX-FP). Once approved by the FDA, rIX-FP (Coagulation Factor IX {Recombinant}, Albumin Fusion Protein) will provide people with hemophilia B and their physicians a long-acting treatment option with dosing intervals up to 14 days.

“As we mentioned at our recent R&D investor briefing, submission of our BLA to the FDA for rIX-FP is a significant milestone for CSL Behring’s recombinant factor IX development program and moves us one step closer to bringing this innovative therapy to hemophilia B patients in the U.S.,” said Dr. Andrew Cuthbertson, Chief Scientific Officer and R&D Director, CSL Limited. “Our strong partnership with and commitment from the hemophilia community led us to develop rIX-FP based on novel recombinant albumin fusion technology. This technology has led to a long-acting treatment candidate that continues our legacy of improving the well-being of patients with bleeding disorders and other rare diseases.”

About PROLONG-9FP Clinical Development Program

CSL Behring’s BLA is based on the results from the PROLONG-9FP Phase II/III (patients ages 12 to 61 years) study. The Phase II/III pivotal study was an open-label, multicenter, safety, pharmacokinetic (PK) and efficacy study of rIX-FP in previously treated patients with severe hemophilia B (FIX ≤ 2%).

This study was designed to compare the change in frequency of spontaneous bleeding events between on-demand treatment and a weekly prophylaxis regimen in patients previously receiving only on-demand treatment; and the number of patients developing inhibitors against factor IX as primary outcome measures. The study evaluated multiple prophylaxis regimens, including 7-day and 14-day intervals. A sub-study evaluated the prevention and control of bleeding in patients with hemophilia B undergoing a surgical procedure.

Study design details for rIX-FP (CSL654) are available at www.clinicaltrials.gov.

About rIX-FP

CSL Behring engineered rIX-FP to extend the half-life of recombinant factor IX through genetic fusion with recombinant albumin. CSL Behring selected recombinant albumin as its recombinant genetic fusion partner for its coagulation factor proteins due to its long physiological half-life. In addition, recombinant albumin has been shown to have a good tolerability profile, low potential for immunogenic reactions and a well-known mechanism of clearance. The cleavable linker connecting recombinant factor IX and recombinant albumin has been specifically designed to preserve the native function of the coagulation factor in the fusion protein, while benefiting from recombinant albumin’s long physiological half-life.

In 2012, the FDA granted Orphan Drug Designation for rIX-FP for the treatment and prophylaxis of bleeding episodes in patients with hemophilia B. The designation includes routine prophylaxis treatment, control and prevention of bleeding episodes, and prevention and control of bleeding in perioperative settings. The FDA’s Orphan Drug Designation program provides orphan status to unique drugs and biologics defined as those intended for the safe and effective treatment or prevention of rare diseases that affect fewer than 200,000 people in the U.S. Orphan designation qualifies the sponsor of the product for important tax credits, elimination of FDA license application fees and certain marketing incentives.

About Hemophilia B

Hemophilia B (congenital factor IX deficiency) is characterized by deficient or defective factor IX and affects approximately 1 in 25,000 to 50,000 people. Hemophilia B is a congenital bleeding disorder characterized by prolonged or spontaneous bleeding, especially into the muscles, joints, or internal organs. Nearly all hemophilia B patients are male.

About CSL Behring

CSL Behring is a leader in the plasma protein therapeutics industry. Committed to saving lives and improving the quality of life for people with rare and serious diseases, the company manufactures and markets a range of plasma-derived and recombinant therapies worldwide.

CSL Behring therapies are used around the world to treat coagulation disorders including hemophilia and von Willebrand disease, primary immune deficiencies, hereditary angioedema and inherited respiratory disease, and neurological disorders in certain markets. The company’s products are also used in cardiac surgery, organ transplantation, burn treatment and to prevent hemolytic disease of the newborn.

CSL Behring operates one of the world’s largest plasma collection networks, CSL Plasma. CSL Behring is a global biopharmaceutical company and a member of the CSL Group of companies. The parent company, CSL Limited (ASX:CSL), is headquartered in Melbourne, Australia. For more information, visit http://www.cslbehring.com.

CSL Behring Starts Pediatric Phase 3 Hemophilia Trial

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CSL Behring Enrolls First Patient in Global Pediatric Phase III Pivotal Study of Recombinant Factor VIII Single Chain (rVIII-SingleChain) to Treat Severe Hemophilia A

King of Prussia, PA — 02 May 2014

CSL Behring today announced that the first patient has been enrolled in the pivotal pediatric phase III study to evaluate the efficacy, safety and pharmacokinetics of its novel investigational recombinant factor VIII single chain (rVIII-SingleChain) for the treatment of previously treated children (up to age 11 years) with severe hemophilia A. The study site for this first enrollment is Malaysia.

A minimum of 25 previously treated subjects from six to 11 years of age and at least 25 subjects under six years of age who have undergone more than 50 exposure days with a previous factor VIII product are planned to be enrolled in this international, multicenter, open-label study. Subjects will be assigned to either an on-demand or prophylaxis treatment regimen for the treatment of bleeding episodes and will receive rVIII-SingleChain at a dose to be determined by the investigator. Hemostatic efficacy will be assessed by the subject or caregiver and the investigator, who will assess overall efficacy by a 4-point scale.

In an earlier study, rVIII-Single Chain showed improved pharmacokinetics over octocog alfa, the comparator, and demonstrated a safety and efficacy profile that supported advancement to late-stage clinical development. CSL Behring, in collaboration with its parent company CSL Limited, is developing rVIII-SingleChain for the treatment of hemophilia A as part of the AFFINITY clinical trial program.

About rVIII-SingleChain
Recombinant FVIII molecules currently available consist of a heavy and a light chain. Under certain conditions, these chains can dissociate, resulting in the formation of separated, or “dissociated,” rFVIII chains that are not hemostatically active. The CSL Behring rVIII-Single Chain uses a strong, covalent bond that connects the light and heavy chains, thereby creating a stable single chain rFVIII.

In-house CSL Behring studies have shown that the molecular integrity of rVIII-SingleChain is significantly increased using the single-chain design, resulting in a homogenous product that is more stable than currently available FVIII products. In addition, in-vitro studies have shown that rVIII-SingleChain demonstrates a strong affinity for von Willebrand factor (VWF), resulting in a faster and more efficient binding to VWF. The FVIII/VWF complex plays an important role in the physiological activity and clearance of FVIII and has been shown to have an influence on the presentation of FVIII to the immune system.

About Hemophilia
Hemophilia is a congenital bleeding disorder characterized by prolonged or spontaneous bleeding, especially into the muscles, joints, or internal organs. In nearly all cases, it affects only males. The disease is caused by deficient or defective blood coagulation proteins known as factor VIII or IX. The most common form of the disease is hemophilia A, or classic hemophilia, in which the clotting factor VIII is either deficient or defective. Hemophilia B is characterized by deficient or defective factor IX. Hemophilia A affects approximately 1 in 5,000 to 10,000 people. Hemophilia B affects approximately 1 in 25,000 to 50,000 people. The recommended treatment for people with hemophilia deficiency is to treat by replacement factor therapy.

About CSL Behring
CSL Behring is a leader in the plasma protein therapeutics industry. Committed to saving lives and improving the quality of life for people with rare and serious diseases, the company manufactures and markets a range of plasma-derived and recombinant therapies worldwide.

CSL Behring therapies are used around the world to treat coagulation disorders including hemophilia and von Willebrand disease, primary immune deficiencies, hereditary angioedema and inherited respiratory disease, and neurological disorders in certain markets. The company’s products are also used in cardiac surgery, organ transplantation, burn treatment and to prevent hemolytic diseases in the newborn. CSL Behring operates one of the world’s largest plasma collection networks, CSL Plasma. CSL Behring is a subsidiary of CSL Limited, a biopharmaceutical with headquarters in Melbourne, Australia. For more information, visit www.cslbehring.com.

###

Contact:
Sheila A. Burke
Director, Communications & Public Relations
Worldwide Commercial Operations
CSL Behring
O: 610-878-4209
Sheila.Burke at cslbehring.com

Original Press release can be found here.

National Outreach for Von Willebrand’s Disease

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NOW Conference video from Feb 2012, Phoenix, AZ

CSL Behring rIX-FP granted Orphan Drug Designation to treat hemophilia B

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Published on June 8, 2012 at 11:49 AM  by NewsMedical

CSL Behring announced today that the company has been granted Orphan Drug Designation by the United States Food and Drug Administration for its novel recombinant fusion protein linking coagulation factor IX with recombinant albumin (rIX-FP). The Orphan Drug Designation is granted for the treatment and prophylaxis of bleeding episodes in patients with congenital factor IX deficiency (hemophilia B). The designation includes routine prophylaxis treatment, control and prevention of bleeding episodes, and prevention and control of bleeding in perioperative settings.

CSL Behring is developing this therapy in collaboration with its parent company CSL Limited (ASX: CSL).

“CSL Behring is pleased to have achieved this important regulatory milestone for our recombinant factor IX,” said Val Romberg, Senior Vice President, Research and Development at CSL Behring. “It represents yet another advance that our company is making in the area of recombinant factor development and is extremely encouraging.”

CSL Behring has engineered rIX-FP to extend the half-life of Factor IX through genetic fusion with recombinant albumin. Albumin has been chosen as the ideal recombinant genetic fusion partner for coagulation factor proteins due to its long physiological half-life. In addition, albumin has been shown to have a good tolerability profile, low potential for immunogenic reactions and a well-known mechanism of clearance compared to some other technologies. The cleavable linker connecting recombinant factor IX and recombinant albumin has been specifically designed to preserve the native function of the coagulation factor in the fusion protein, while benefiting from recombinant albumin’s long physiological half-life.

The FDA’s Orphan Drug Designation program provides orphan status to unique drugs and biologics, defined as those intended for the safe and effective treatment or prevention of rare diseases that affect fewer than 200,000 people in the U.S.

SOURCE CSL Behring

Do You Know the Signs and Symptoms of von Willebrand Disease (VWD)?

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Leading Health Information Source for Women Introduces Educational Materials About Most Common Bleeding Disorder

 RED BANK, N.J., April 18, 2012 /PRNewswire/ — Although von Willebrand disease (VWD) is the most common hereditary bleeding disorder in the United States, affecting up to 1 percent of the population, it is often misdiagnosed or under-diagnosed in women. HealthyWomen, the nation’s leading nonprofit health information source for women, has developed new educational materials they hope will shine a light on a disorder that, when undiagnosed and untreated, can severely impact the quality of life for women. 

Caused when von Willebrand factor, a protein in the blood that is necessary for clotting, is either missing or not working properly, VWD affects men and women equally. Yet, when undiagnosed and untreated in women, it puts them at a greater risk for life-threatening bleeding following childbirth and for undergoing unnecessary hysterectomies.  

“Undiagnosed bleeding disorders, like von Willebrand disease, can have real health consequences for women,” said Elizabeth Battaglino Cahill, RN, executive director of HealthyWomen. “The goal of these new materials, available on HealthyWomen.org, is to spark honest conversations among mothers, sisters and daughters about the signs and symptoms of VWD and to hopefully underscore the need for even more education about this condition.”

The five signs and symptoms of von Willebrand disease are:

  • Easy bruising
  • Frequent or prolonged nosebleeds
  • Heavy, prolonged menstruation
  • Prolonged bleeding following injury or surgery
  • Prolonged bleeding during dental procedures

“Because VWD is a hereditary disorder, many women dismiss tell-tale signs like easy bruising or heavy periods as normal because their mother or other female relatives experienced similar symptoms,” said Meera Chitlur, M.D., Director, Hemophilia Treatment Center and Hemostasis Program, Children’s Hospital of Michigan and who also works with the Foundation for Women & Girls with Blood Disorders (FWGBD), a non-profit advocacy and education organization dedicated to advancing physician and healthcare provider knowledge of the unique needs and challenges faced by women and adolescent girls with blood disorders.  “Unexplained bleeding or bruising is not normal and is something you should always discuss with your healthcare provider. If you are diagnosed with a bleeding disorder, treatments are available.”

The new materials include common questions about VWD answered by an expert, as well as real-life stories of women living with the condition. One of these women, Kristin Prior, 49, recalls her own diagnosis in 1996.

“While I had experienced many of the five signs and symptoms throughout early adulthood it wasn’t until I was 32 that I finally received my diagnosis of von Willebrand disease,” said Prior. “My hope is that women who are facing some of the same challenges that I did will read my story on HealthyWomen.org and realize that diagnosis and treatment can make a tremendous difference in their lives.”  

The von Willebrand disease educational resources were developed through an educational grant from CSL Behring, a world leader in developing and manufacturing safe and effective solutions to treat and manage bleeding disorders.

About HealthyWomen

HealthyWomen (HW) is the nation’s leading nonprofit health information source for women. For more than 20 years, women have been coming to HW for answers to their most pressing and personal health care questions. HW provides health information through a wide array of online content and print publications that are original, objective and reviewed and approved by medical experts. Its website, http://www.HealthyWomen.org®, was recognized by ForbesWoman as one of the “Top 100 Websites for Women” in 2010 and 2011 and was named the top women’s health website by Dr. Mehmet Oz in O, The Oprah Magazine. To learn more, visit www.HealthyWomen.org.

About the Foundation for Women & Girls with Blood Disorders

The Foundation for Women & Girls with Blood Disorders (FWGBD) is a non-profit advocacy and education organization dedicated to advancing physician and healthcare provider knowledge of the unique needs and challenges faced by women and adolescent girls with blood disorders.  Founded in 2010, the Foundation’s mission is to ensure that all women and adolescent girls with blood disorders are correctly diagnosed and optimally treated and managed at every life stage.  For more information, please visit www.fwgbd.org.

About CSL Behring

CSL Behring is a leader in the plasma protein therapeutics industry. Committed to saving lives and improving the quality of life for people with rare and serious diseases, the company manufactures and markets a range of plasma-derived and recombinant therapies worldwide. CSL Behring therapies are indicated for the treatment of coagulation disorders including hemophilia and von Willebrand disease, primary immune deficiencies, hereditary angioedema and inherited respiratory disease. The company’s products are also used in cardiac surgery, organ transplantation, burn treatment and to prevent hemolytic diseases in newborns. CSL Behring operates one of the world’s largest plasma collection networks, CSL Plasma. CSL Behring is a subsidiary of CSL Limited (ASX: CSL), a biopharmaceutical company headquartered in Melbourne, Australia. For more information, visit http://www.cslbehring.com/.

Contact

Erin Graves, Director of Communications and New Media
HealthyWomen
(732) 978-4947
egraves@HealthyWomen.org

Lauren Abel
MCS Public Relations on behalf of HealthyWomen and CSL Behring
(800) 477-9626
laurena@mcspr.com

 

SOURCE HealthyWomen

For Original Article click here.

CSL Behring Commences Phase I Study With rVIIa-FP

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Phase I Study With rVIIa-FP, a Novel Therapy to Treat People With Hemophilia A and Hemophilia B Who Have Inhibitors

31 Mar 2012

KING OF PRUSSIA, PA, USA – March 30, 2012 – CSL Behring announced today the first in human dosing of recombinant fusion protein linking coagulation factor VIIa with albumin (rVIIa-FP). The Phase I study will investigate in healthy volunteers the safety and pharmacokinetics of rVIIa-FP in comparison to placebo. CSL Behring, in collaboration with its parent company, CSL Limited (ASX: CSL.AX – News), is developing rVIIa-FP, a novel therapy to treat hemophilia A and hemophilia B patients who have inhibitors as part of the PROLONG 7- FP clinical study program. For more information about this study, please see www.clinicaltrials.gov.

CSL Behring’s albumin fusion technology uses albumin as the ideal recombinant genetic fusion partner for coagulation factor proteins due to its inherently long half-life, high potential for tolerability, known mechanism of clearance and low potential for immunogenic reactions. CSL Behring’s rVIIa albumin fusion protein is expected to exhibit a good tolerability profile and improved pharmacokinetics that may enable prophylaxis.

CSL Behring’s rVIIa-FP was previously granted Orphan Drug Designation by the European Commission and the United States Food and Drug Administration.

About Hemophilia
Hemophilia is a congenital bleeding disorder characterized by prolonged or spontaneous bleeding, especially into the muscles, joints, or internal organs. In nearly all cases, it affects only males. The disease is caused by deficient or defective blood coagulation proteins known as factor VIII or IX. The most common form of the disease is hemophilia A, or classic hemophilia, in which the clotting factor VIII is either deficient or defective. Hemophilia B is characterized by deficient or defective factor IX. Hemophilia A affects approximately 1 in 5,000 to 10,000 people. Hemophilia B affects approximately 1 in 25,000 to 50,000 people. The recommended treatment for patients who are factor deficient is to treat by replacement factor therapy. A complication in some patients is the development of inhibitory antibodies (inhibitors) to FVIII or FIX which render replacement therapy ineffective. This can occur in up to 25 percent of hemophilia A patients and approximately 5 percent of hemophilia B patients. One treatment option for these patients is recombinant activated factor VII (called a “bypassing agent”) which can be used to achieve hemostasis without the need for factor VIII or IX.

About the recombinant fusion protein linking coagulation factor VIIa with recombinant albumin (rVIIa-FP)
Preclinical studies have confirmed that CSL Behring’s rVIIa-FP has favorable pharmacokinetic properties compared with the existing recombinant FVIIa product. Significant increases in half-life have been observed across all animal species. The use of a bypassing agent with an extended half-life could offer significant benefit to those affected by hemophilia A or B with inhibitors and may offer patients the opportunity to be treated less frequently than with the currently available product.

CSL Behring’s clinical program intends to demonstrate that an extended half-life rVIIa-FP will result in a requirement for fewer doses while providing adequate therapeutic response in patients with hemophilia A and B with inhibitors.

About CSL Behring
CSL Behring is a leader in the plasma protein therapeutics industry. Committed to saving lives and improving the quality of life for people with rare and serious diseases, the company manufactures and markets a range of plasma-derived and recombinant therapies worldwide. CSL Behring therapies are indicated for the treatment of coagulation disorders including hemophilia and von Willebrand disease, primary immune deficiencies, hereditary angioedema and inherited respiratory disease. The company’s products are also used in cardiac surgery, organ transplantation, burn treatment and to prevent hemolytic disease of the newborn. CSL Behring operates one of the world’s largest plasma collection networks, CSL Plasma. CSL Behring is a subsidiary of CSL Limited (ASX:CSL.AX – News), a biopharmaceutical company headquartered in Melbourne, Australia. For information: http://www.cslbehring.com.

SOURCE: CSL Behring

More new drugs are in the pipeline now than in past decades

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By Sarah Aldridge | 02.09.2012  by Hemaware

The marketing terms “new and improved” and “longer lasting” are not limited to the latest brand of chewing gum. They also apply to a long list of therapies now in clinical trials for people with bleeding disorders. Some people have waited years for a new recombinant product; others a lifetime for any factor product to treat their rare condition. For many, their patience is about to pay off.

There are more drugs in the pipeline now than in the past few decades. “The companies’ commitment to continue to work on behalf of patients with bleeding disorders is what’s driving it,” says Val D. Bias, CEO of the National Hemophilia Foundation (NHF). The dilemma facing many patients in the future won’t be a lack of medications, but a plethora of products that act in a variety of ways. (See table “Bleeding Disorders Drugs in Human Clinical Trials.”)

For drugs to be approved and licensed by the US Food and Drug Administration (FDA), they have to go through a series of clinical trials. First they are tested on animals, such as mice; then they are tested on humans. Each phase of a clinical trial helps determine the drug’s safety, efficacy, optimal dosage and side effects. (See sidebar, “Clinical Trial Phases.”) The National Institutes of Health clinical trials registry at clinicaltrials.gov lists more than 250 trials on hemophilia and more than 60 on von Willebrand disease (VWD). (See “Clinical Trials 101.”).)

Tried and True vs. Something New

Prophylactic medications to treat hemophilia have given patients a new degree of freedom. They can self-infuse whenever and wherever it’s convenient.

“In terms of hemophilia A and B, I feel that the products we have right now are really good,” says Marion Koerper, MD, NHF medical advisor. She is also director emerita of the hemophilia treatment center at the University of California, San Francisco, where she practices pediatric hematology and oncology. “The factors do work to stop bleeding or, in the case of prophylaxis, prevent bleeding.”

However, prophylaxis is not perfect. “It’s only efficacious if the patient takes it the prescribed way,” Koerper says. The best time to give factor is in the morning before school or work, often the most hectic time of day. For busy families who delay treatment until bedtime, there are consequences. “That is not optimal because the child’s highest levels are while he’s asleep, rather than when he’s running around with his pals on the playground,” says Koerper.

Further, taking a product two or three times a week means that clotting strength can plummet on the off days. “When we give prophylaxis right now for a hemophilia A patient, we’re resolved to the fact that before their next prophy dose, their level in plasma could be as low as about 1% to 2%,” says Steven W. Pipe, MD, medical director, Pediatric Hemophilia and Coagulation Disorders Program, University of Michigan, Ann Arbor. That puts patients at risk for bleeding, especially if there is trauma. “Clearly, that’s not correction of their hemostasis.”

Products With Staying Power

To remedy that risk, pharmaceutical companies are creating new products that last longer in the bloodstream. The amount of factor VIII (FVIII) or factor FIX (FIX) in the blood is measured by its half-life, the time it takes for the amount of factor to be reduced by half. There are many variables involved, including blood type, but FVIII’s half-life is about 8–12 hours; FIX’s is about 18–24 hours. One option is to increase the interval between prophylactic doses, ideally to once a week for FIX products and twice a week for FVIII products. 

Another option is to retain the current prophylactic regimen, but avoid the precipitous drop in clotting factor as the next dosing time approaches. “We may be able to maintain much higher plasma levels than we’ve been able to previously with the same intervals that we’re currently using,” says Pipe.

One way to prevent factor products from degrading too quickly is to attach them to the chemical compound polyethylene glycol (PEG). This process, called PEGylation, increases the size of the factor protein molecule so that it circulates in the blood longer and is not cleared by the kidneys prematurely.

“Another strategy is to fuse the recombinant factor protein molecule to a partner protein that already has a long half-life,” says Pipe. Two naturally occurring partner proteins being fused to the FVIII or FIX molecule are albumin, which moves small molecules through the bloodstream, and Fc, a protein fragment that facilitates binding and recycling of immunoglobulin G (IgG).

Data from early clinical trials on Biogen Idec’s recombinant FVIII and FIX Fc fusion products, rFVIIIFc and rFIXFc, look promising. The A-LONG study on patients with severe hemophilia A showed a 1.7-fold increase in half-life during phase 1/2a clinical trials. B-LONG studies on patients with severe hemophilia B showed a nearly threefold increase in half-life during phase 1/2 trials. (See “Long Strides,” HemAware Summer 2011, p. 14.)

Adjunctive therapies, or drugs that are added to the primary factor product, are also being tested in clinical trials. Some use molecules that bind to tissue factor pathway inhibitor (TFPI), preventing it from hindering the action of FXa and thrombin, necessary for clot initiation and formation. Baxter’s BAX513 uses fucoidan, a seaweed extract being tested on healthy volunteers without hemophilia.

“If you block the proteins that are slowing down coagulation, you can actually restore normal clotting in hemophilic plasma without replacing the missing clotting factor,” says Pipe. For some patients, the adjunctive therapy may become the primary therapy, reducing the number of infusions needed, he says. A bonus is that some TFPI antagonists could be taken orally, such as the capsule form that delivered fucoidan to trial subjects.

“Compliance with bleeding disorders’ treatment is always an issue,” says Bias. “A drug that works better, faster and that you have to take less often can only improve that.”

Innovations for Inhibitors

An estimated 25% of patients with severe hemophilia A develop antibodies, called inhibitors, to the infused factor. Currently, patients undergo immune tolerance therapy to desensitize their immune systems or take a bypassing agent, such as FVIIa. The main drawbacks of the recombinant FVIIa product are that its half-life is only two hours and it is very expensive.

Inspiration Biopharmaceuticals is developing a recombinant porcine (pig) FVIII product for patients with inhibitors. “You can give a dose and get the measurable level of FVIII. That’s a distinct advantage when there’s a life-threatening­ bleed, like a head bleed (intracranial hemorrhage), or a limb-threatening bleed in someone with a compartment syndrome (increased pressure in a muscle in an enclosed space),” Koerper says. But because 80% of patients developed antibodies to plasma-derived pig factor within five days or after five doses, it is possible that a similar scenario might occur with the recombinant product. Results of the clinical trials will provide more data, but its use will probably be restricted.

The longer-lasting products may have an added benefit for inhibitor patients. “Some forms of PEGylation strategy and possibly even some of the fusion proteins may result in reduced risk for inhibitors,” says Pipe. Another product now being tested, Octapharma’s recombinant human-cl rhFVIII, may reduce the rate of inhibitor development because it uses proteins from human cells, not the typical hamster cells.

Recombinant VWD Product at Last

Recombinant products to treat FVIII and FIX were approved in 1992 and 1998, respectively; not so for von Willebrand factor (VWF). “It has bothered me for almost 20 years that I couldn’t offer a recombinant VWF product to my VWD patients,” says Koerper. That need will be fulfilled once Baxter’s recombinant VWF product goes through FDA approval and licensure. It will be targeted to patients with type 3 VWD, the most severe form, and those unresponsive to DDAVP, a synthetic hormone used to prevent or stop bleeds.

Gene Therapy Revisited

Researchers can now create precision drugs that treat diseases caused by specific genetic mutations. One such drug in phase 2 trials is Ataluren (PTC 124®), manufactured by PTC Therapeutics Inc. It will be used for the approximately 10%–15% of patients with hemophilia A and B with a nonsense mutation, which halts factor production early. Ataluren introduces a molecule that allows the cell to read through the stop signal, making more clotting factor. It comes in a powder that is mixed in water. “Something that you can swallow is going to be a huge advantage because there are no needles involved,” Koerper says. (See sidebar “The Allure of Ataluren” in “What’s Your Genotype?” HemAware Spring 2010, p. 29.)

Rare Bleeding Disorders on the Radar

Patients with rare factor deficiencies know that being one in a million is hardly a cause for celebration. “People forget that there are other clotting factor deficiencies that, in some cases, have no treatment,” says Bias.

But hope is on the horizon. Companies that fractionate, or separate, plasma are interested in getting as many products out of it as they can, says Pipe. “Developing new markets for new plasma derivatives, such as the new FXIII product Corifact™ (approved by the FDA in March 2011), and RiaSTAP®, a fibrinogen concentrate to treat FI deficiency (indicated for patients with congenital fibrinogen deficiency including afibrinogenemia and hypofibrinogenemia only), increases the sustainability and viability of the plasma fractionation industry.” Both products are manufactured by CSL Behring. Currently, Novo Nordisk has applied for a license for its recombinant FXIII product. British Plasma Laboratories has a plasma-derived FX product in phase 3 clinical trials.

“NHF is most supportive of new products for rare disorders or categories where products don’t currently exist, like the recombinant VWD product,” Bias says. “It’s important that people have access to a product that’s made for them.”

Time Frame for Trials

For drugs now in clinical trials, that access may take a few years. “From initiation of clinical trials to approval, it’s about a five-year window,” says Pipe. Drugs nearing the finish line—those in phase 3 or moving to FDA licensing—still have between 18 and 30 months, he says.

New Era of Optimism

Patients awaiting better, more effective or first-time products to treat their bleeding disorders have many reasons to be optimistic. “For the first time we’re now going to be offering agents that clearly behave differently. We’re not going to be faced with just a single-breed entity to choose from,” Pipe says.

The idea of having more distinct options may be foreign to some, but should be very welcome. New products with different mechanisms mean that treatments may soon be given in a more targeted, personalized manner. “When you have multiple choices it’s going to take some time for the clinicians and families to figure out what’s best for individual patients,” Pipe says.

When recombinant FVIII and FIX drugs came out two decades ago, Koerper thought they were the “ultimate products.” But with all of these recent innovations, she’s changed her thinking. “Now I realize there is so much more that can be done.”

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Clinical Trial Phases

A drug must go through several stages of testing, called “phases” in clinical trials, before it can seek approval review by the Food and Drug Administration (FDA) for use in the US. Depending on how well things go in each phase, the drug progresses from one phase to the next. However, some drug trials are halted voluntarily or by the FDA at certain stages because of concerns about safety or efficacy, for instance. It can take up to five years or more for a new drug to pass muster and make it to the marketplace.

Phase 1

An experimental drug is given to a small number of people (20–100*) to test its safety, tolerability, pharmacokinetics (absorption, distribution, metabolism and excretion) and pharmacodynamics (biochemistry and physiology). Dose-escalating studies are done during this phase to find the optimal dosage.

Phase 2

The drug is given to a larger number of people (100–300*) to evaluate its effectiveness and safety.

Phase 3

The drug is tested in an even larger group of people (1,000–3,000*) at multiple centers across the country to confirm its effectiveness and safety compared with current treatments. During this phase, side effects are also monitored. The studies are randomized and controlled, meaning some patients receive the drug and others get a placebo. Once this “pivotal phase” is successfully completed, the manufacturer can apply for licensing review by the FDA.

Phase 4

Once a drug is licensed for sale, post-marketing surveillance trials are required by the FDA. These trials provide important information on risks, including less common side effects, benefits and optimal use.

*Note: these figures are for standard clinical trials. For bleeding disorders products, the number of trial subjects is often much smaller.

Information partially adapted from clinicaltrials.gov.

Bleeding Disorders Drugs in Human Clinical Trials*

Bleeding Disorder Drug Name Company Clinical Trial
Hemophilia A Recombinant FVIII-Fc Fusion Biogen Idec Phase 3
  NN7088 Recombinant FVIII, third generation Novo Nordisk Phase 3
  Human-cl rhFVIII (recomb FVIII, human cell line) Octapharma Phase 3
  OBI-1 Recombinant Porcine FVIII Inspiration Phase 2/3
  ARC 19499 PEG-conjugated aptamer Archemix Phase 1/2
  BAX499 FVIII, subcutaneous Baxter Phase 1
  CSL627 Recombinant FVIII-single chain CSL Behring Phase 1
Hemophilia B BAX326 Recombinant FIX Baxter Phase 3
  Recombinant FIX-Fc Fusion Biogen Idec Phase 3
  OB1001 Recombinant FIX Inspiration Phase 2/3
  NN7999 Glyco-PEGylated Recombinant FIX Novo Nordisk Phase 3
  ARC 19499 PEG-conjugated aptamer Archemix Phase 1/2
  BAX499 FIX, subcutaneous Baxter Phase 1
  CSL654 Recombinant FIX-Albumin Fusion CSL Behring Phase 1/2
Hemophilia A & B
Nonsense mutation
PTC 124 Ataluren PTC Phase 2
Inhibitors rFVII analog Novo Nordisk Phase 3
  CSL689 Recombinant FVII-Albumin Fusion CSL Behring Phase 2
  GlycoPEG-rFVIIa Novo Nordisk Phase 2
  SQ GlycoPEG-rFVIIa Novo Nordisk Phase 1
Von Willebrand Disease BAX 111, rVWF Baxter Phase 3
Rare Factor Deficiencies Recombinant FXIII Novo Nordisk License applied for
  Plasma-derived FX BPL Phase 3

*This table provides a sampling of drugs now in clinical trials to treat various bleeding disorders. It is by no means comprehensive. NHF does not endorse or recommend any of the products or manufacturers listed. To check the status of drugs now in clinical trials, visit clinicaltrials.gov.

Search this blog for more information on individual press releases form Baxter, Novo Nordisk, CSL Behring,  OctaPharma, Biogen Idec, and Isporation Biopharmaceuticals.

First patient screened in CSL Behring global Phase I/III study of recombinant single-chain factor VIII

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Vienna, Austria — 24 February 2012

CSL Behring has announced that the first patient has been screened in its recombinant coagulation single-chain factor VIII (rFVIII) trial, part of the AFFINITY clinical trial program. The CSL Behring rFVIII, called ‘rVIII-SingleChain’, is a novel molecule being studied for the treatment of hemophilia A. It is being developed by CSL Behring, in collaboration with its parent company, CSL Limited (ASX:CSL).

“CSL is advancing at a very encouraging rate with our recombinant coagulation factor development program,” said Dr. Andrew Cuthbertson, Chief Scientist CSL Limited. “Our ongoing commitment to providing safe and effective therapies to help improve the lives of those affected by hemophilia A and other rare bleeding disorders is being fulfilled with each milestone we reach. Our recombinant coagulation single-chain factor VIII molecule is showing strong promise. We look forward with excitement to seeing results of the phase I/III study in coming months.”

About the AFFINITY Phase I/III Study
The Phase I/III study is an open-label, multicenter trial that examines the crossover safety, efficacy and pharmacokinetics of recombinant coagulation single-chain factor VIII compared with recombinant human antihemophilic factor VIII (octocog alpha).

In Part 1 of the study, subjects will receive a single infusion of 50 IU/kg of octocog alpha followed by a single infusion of 50 IU/kg. In Parts 2 and 3 of the study, subjects will receive infusions of rVIII-SingleChain to prevent and treat bleeding (if required), at a dose and frequency determined by their study doctor (based on the subject’s underlying bleeding phenotype). More information about the study design can be found at www.clinicaltrials.gov.

Recombinant single-chain factor VIII consists of two linked protein chains – a heavy one and a light one. Under certain conditions, these chains can dissociate, resulting in the formation of separated, or “dissociated,” rFVIII chains. The CSL Behring rVIII-SingleChain uses a strong, covalent bond that connects the light and heavy chains, thereby creating a single chain rFVIII.

In-house studies have shown that the molecular integrity of rVIII-SingleChain is significantly increased using the single-chain design, resulting in a homogenous product that is more stable than currently available FVIII products. In addition, in-vitro studies have shown that rVIII-SingleChain demonstrates a very strong affinity for von Willebrand factor, resulting in a faster and more efficient binding to VWF. The FVIII/VWF complex plays an important role in the physiological activity and clearance of FVIII and has been shown to have an influence on the presentation of FVIII to the immune system.

The research leading to the initiation of the studies that CSL Behring is now conducting is the result of collaboration across the CSL Behring research sites in Marburg, Germany, in King of Prussia, USA, and at laboratories operated by CSL Limited in Melbourne, Australia.

About Hemophilia
Hemophilia is a congenital bleeding disorder characterized by prolonged or spontaneous bleeding, especially into the muscles, joints, or internal organs. In nearly all cases, it affects only males. The disease is caused by deficient or defective blood coagulation proteins known as factor VIII or IX. The most common form of the disease is hemophilia A, or classic hemophilia, in which the clotting factor VIII is either deficient or defective. Hemophilia B is characterized by deficient or defective factor IX. Hemophilia A affects approximately 1 in 5,000 to 10,000 people. Hemophilia B affects approximately 1 in 25,000 to 50,000 people. The recommended treatment for patients who are factor deficient is to treat by replacement factor therapy. A complication in some patients is the development of inhibitory antibodies (inhibitors) to FVIII or FIX which renders replacement therapy ineffective. This can occur in up to 25 percent of hemophilia A patients and around 5 percent of hemophilia B patients. One treatment option for these patients is recombinant activated factor VII (called a bypassing agent) that can be used to achieve hemostasis without the need for factor VIII or IX.

About CSL Behring
CSL Behring is a leader in the plasma protein therapeutics industry. Committed to saving lives and improving the quality of life for people with rare and serious diseases, the company manufactures and markets a range of plasma-derived and recombinant therapies worldwide. CSL Behring therapies are indicated for the treatment of coagulation disorders including hemophilia and von Willebrand disease, primary immune deficiencies, hereditary angioedema and inherited respiratory disease. The company’s products are also used in cardiac surgery, organ transplantation, burn treatment and to prevent hemolytic diseases in newborns. CSL Behring operates one of the world’s largest plasma collection networks, CSL Plasma. CSL Behring is a subsidiary of CSL Limited (ASX:CSL), a biopharmaceutical company headquartered in Melbourne, Australia. For more information, visit www.cslbehring.com.

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Media Contact:
Sheila Burke
Worldwide Commercial Communications & Public Relations
CSL Behring
610-878-4209

Press release – Click here.

CSL Behring Receives FDA Orphan Drug Designation for rVIIa-FP

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KING OF PRUSSIA, Pa., Feb. 16, 2012 /PRNewswire/ — CSL Behring announced today that the company has been granted orphan drug designation by the U.S. Food and Drug Administration (FDA) for its novel recombinant fusion protein linking coagulation factor VIIa with albumin (rVIIa-FP). The Orphan Drug Designation is granted for the treatment and prophylaxis of bleeding episodes in patients with congenital hemophilia and inhibitors to coagulation factor VIII or IX. CSL Behring is developing this therapy in collaboration with its parent company CSL Limited (ASX: CSL).

The CSL Behring rVIIa-FP clinical program will soon be initiated and intends to demonstrate that an extended half-life rVIIa-FP will result in a requirement for fewer doses while providing adequate therapeutic response in patients who have hemophilia A and B with inhibitors.

“CSL Behring’s albumin fusion technology uses albumin as the ideal recombinant genetic fusion partner for coagulation factor proteins because of its high tolerability, inherently long half-life, low potential for immunogenic reactions and known mechanism of clearance,” said Russell Basser, M.D., Senior Vice President, Global Clinical R&D at CSL Behring. “CSL Behring’s rVIIa albumin fusion protein is expected to exhibit a good tolerability profile and improved pharmacokinetics that may enable prophylaxis. We welcome Orphan Drug Designation for our rVIIa-FP and will work closely with the FDA to make this important therapy available for people in the U.S. with hemophilia A and hemophilia B with inhibitors.”

The FDA’s Orphan Drug Designation program provides orphan status to unique drugs and biologics, defined as those intended for the safe and effective treatment or prevention of rare diseases that affect fewer than 200,000 people in the U.S. Orphan designation qualifies the sponsor of the product for important tax credits, elimination of FDA license application fees and certain marketing incentives.

CSL Behring’s rVIIa-FP was granted Orphan Drug Designations (ODD) by the European Commission in May, 2011.

About Hemophilia
Hemophilia is a congenital bleeding disorder characterized by prolonged or spontaneous bleeding, especially into the muscles, joints, or internal organs. In nearly all cases, it affects only males. The disease is caused by deficient or defective blood coagulation proteins known as factor VIII or IX. The most common form of the disease is hemophilia A, or classic hemophilia, in which the clotting factor VIII is either deficient or defective.  Hemophilia B is characterized by deficient or defective factor IX. Hemophilia A affects approximately 1 in 5,000 to 10,000 people. Hemophilia B affects approximately 1 in 25,000 to 50,000 people. The recommended treatment for patients who are factor deficient is to treat by replacement factor therapy. A complication in some patients is the development of inhibitory antibodies (inhibitors) to FVIII or FIX which renders replacement therapy ineffective.  This can occur in up to 25 percent of hemophilia A patients and around 5 percent of hemophilia B patients.  One treatment option for these patients is recombinant activated factor VII (called a bypassing agent) which can be used to achieve hemostasis without the need for factor VIII or IX. 

About the recombinant fusion protein linking coagulation factor VIIa with albumin (rVIIa-FP)
Preclinical studies have confirmed that CSL Behring’s rVIIa-FP has favorable pharmacokinetic properties compared with the existing recombinant FVIIa product. Significant increases in half-life have been observed across all animal species. The use of a bypassing agent with an extended half-life could offer significant benefit to those affected by hemophilia A or B with inhibitors and may offer patients the opportunity to be treated less frequently than with currently available product.

About CSL Behring
CSL Behring is a leader in the plasma protein therapeutics industry. Committed to saving lives and improving the quality of life for people with rare and serious diseases, the company manufactures and markets a range of plasma-derived and recombinant therapies worldwide. CSL Behring therapies are indicated for the treatment of coagulation disorders including hemophilia and von Willebrand disease, primary immune deficiencies, hereditary angioedema and inherited respiratory disease. The company’s products are also used in cardiac surgery, organ transplantation, burn treatment and to prevent hemolytic diseases in newborns. CSL Behring operates one of the world’s largest plasma collection networks, CSL Plasma. CSL Behring is a subsidiary of CSL Limited (ASX:CSL), a biopharmaceutical company headquartered in Melbourne, Australia. For more information, visit www.cslbehring.com.

For Press release click here.

SOURCE CSL Behring

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