Adults and adolescents with hemophilia A had well controlled bleeding when dosed two or three times weekly with recombinant factor VIII single chain (rVIII-SingleChain), according to a 

 presented during the Late Breaking Session at the 2015 International Society  on Thrombosis and Haemostasis Congress.

Researchers from CSL Behring compared octocog alfa and the novel investigational rVIII-SingleChain in order to test the continuation of dosing safety and efficacy for adults and adolescents with hemophilia A. More than 14,000 exposure days in 146 prophylaxis patients and 27 patients with on demand treatment were included in the study. The researchers treated 120 patients for more than 50 days of exposure, and there were 52 patients with more than 100 days of exposure. About a third of the prophylaxis group was dosed twice weekly and about half received three times weekly dosing.

The rVIII-SingleChain patients had low annualized bleeding rates (ABR), with a median ABR of 1.14 and an annualized spontaneous bleeding rate (AsBR) of 0.00, the researchers found. When compared to octocog alfa, the researchers said rVIII-SingleChain demonstrated improved pharmacokinetic parameters. The investigators treated 848 bleeds throughout the course of the study, 94 percent of which were successfully controlled with no more than two doses of rVIII-SingleChain, and 81 percent of bleeds were controlled with just one infusion.

“We observed relatively low ABR and a median of zero spontaneous bleeding events with rVIII-SingleChain for routine prophylaxis for patients with hemophilia A,” lead investigator Professor Ingrid Pabinger-Fasching, MD, of the Medical University of Vienna, Austria, explained in a 

. “As the first and only single chain recombinant factor product, rVIII-SingleChain has the potential to offer improved protection from bleeding with less frequent dosing, and an excellent safety profile thus far.”

The researchers said that the most common adverse events in the rVIII-SingleChain treatment group were naso pharyngitis, arthralgia, and headache.

The investigators treated 94 percent, or 835 bleeds, with rVIII-SingleChain and rated the control as “excellent” or “good.” The research was part of a larger study, the Affinity Phase I/ III study, which is an open label, multicenter trial examining the safety, efficacy, and pharmacokinetics of rVIII-SingleChain compared to octocog alfa.

“Our novel rVIII-SingleChain was specifically designed to improve the stability and provide longer lasting hemostatic efficacy of factor VIII, thereby addressing the need to provide hemophilia A patients with a treatment that may require fewer infusions while maintaining its therapeutic effect,” Dr. Andrew Cuthbertson, Chief Scientific Officer and Director of R&D, CSL Limited, continued in the statement. “These pivotal data are promising and are supportive of CSL Behring’s commitment to bringing this therapy to the market, and to helping improve the care of people living with hemophilia A.”

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Researchers reported that adults and adolescents with hemophilia A had well controlled bleeding when dosed two or three times weekly with recombinant factor VIII single chain (rVIII-SingleChain).

Well-Controlled Bleeding with rVIII-SingleChain

In May, Qizhen Shi, MD, PhD, of the Medical College of Wisconsin in Milwaukee received a four year, $1.5 million grant from the National Institutes of Health’s National Heart, Lung, and Blood institute. The grant is to continue Shi’s work in researching blood platelet gene therapies for the treatment of hemophilia A.

Shi is also an investigator at the Blood Research Institute at BloodCenter of Wisconson, where she focuses on finding therapies for hemophilia A patients. Previously, Shi has worked on therapies including inactivating antibodies. According to a 

, the investigative team discovered a clinically translatable gene therapy protocol, which is a gene delivery system that introduced the production of therapeutic clotting proteins in platelets, so that the inhibition of inactivating antibodies is avoided.

“The development of inhibitory antibodies against [blood clotting factors] is not only a severe and important complication of protein replacement therapy, but also a major concern in gene therapy of hemophilia A,” Shi continued in the press release. “Generation of such inhibitors might potentially preclude gene therapy for hemophilia A. In this project, we propose to investigate a novel gene therapy approach that will provide therapeutic FVIII protein and induce immune tolerance for hemophilia A.”

At the International Society on Thrombosis and Haemostasis Congress in Toronto, Canada in June, Shi was also recognized with the Bayer Hemophilia Award. Shi was one of 17 hemophilia investigations around the globe to receive the grant as part of the Bayer Hemophilia Award Program (BHAP).

BHAP grants are intended to provide funds to investigate various projects, including nanomedicines, new methods to improve inhibitor detection in hemophilia patients, platelet gene therapy, and bioengineering factor VIII replacement therapy, a second 

 stated. Shi’s team intends to use the grant to test whether virus mediated platelet specific gene transfer can introduce immune tolerance in hemophilia B mice with inhibitors and provide therapeutic factor IX proteins, the statement continued.

“I’m honored to be selected as a 2015 BHAP award winner,” Shi said at the time. “The support from Bayer will help me continue my research into the role gene therapy might potentially play in helping patients manage their hemophilia.”

Shi added that the research the team plans to conduct research which they believe could be promising for gene therapy targets for hemophilia B patients, including those with inhibitors.

Researchers discovered a clinically translatable gene therapy protocol, which is a gene delivery system that introduced the production of therapeutic clotting proteins in platelets, so that the inhibition of inactivating antibodies is avoided.

Two Grants Awarded to Medical College of Wisconsin Researcher

Over the past few months, the Food and Drug Administration (FDA) approved several drugs for the control and prevention of bleeding episodes in patients with hemophilia. Other drug classifications granted included Orphan Drug Status and Breakthrough Therapy designation.

In April, the FDA approved a recombinant factor (rFIX) product called Ixinity (Emergent BioSolutions, Inc.) for the control and prevention of bleeding episodes in patients aged 12 years or older with hemophilia B. The drug is also designed for perioperative management of hemophilia B. In Phase I and III trials, 84 percent of moderate to severe hemophilia B patients had bleeds resolved which was patient rated as “excellent” or “good.” The researchers used “excellent” to encompass dramatic response with abrupt pain relief and clear reduction in joint or hemorrhage site size, while “good” was defined as pain relief or reduction in hemorrhage site size. In “good” responses, an additional infusion may have been required for bleed resolution. The pharmacokinetic results demonstrated that Ixinity achieved similar behavior to other licensed recombinant coagulation FIX products on the market.

Another drug, ATX-F8-117 (brand name Apitope), was granted Orphan Drug Status by the FDA in June. The drug is designed to prevent or treat inhibitors in hemophilia A patients who have inhibitors or are at risk for producing inhibitors. The European Medical Agency previously granted Orphan Drug Status to Apitope in order to allow factor VIII (FVIII) inhibitor treatment to be developed.

In early September, the FDA granted breakthrough therapy designation to ACE910, a prophylactic treatment with hemophilia A patients aged 12 or older. The artificial protein is designed to bond factor proteins IXa and X — mimicking a function that FVIII completes – and act as a clotting factor. The therapy should work regardless if the hemophilia patients have developed inhibitor antibodies to FVIII. The researchers highlighted that the patients would not likely develop new FVIII inhibitors because ACE910 is so structurally different than FVIII.

Nuwiq, from Octapharma USA, was approved by the FDA for use as an recombinant factor for adults and children with hemophilia A. The drug is designed for on demand treatment and control of bleeding episodes as well as perioperative management of bleeding. The FDA approval was based on a study of 32 adults where prophylactic efficacy reached an “excellent” or “good” rating in nearly all (92 percent) of patients. And again, for nearly all (94 percent) of patients, on demand treatment with Nuwiq was rated “excellent” or “good.”

Over the past few months, the Food and Drug Administration (FDA) approved several drugs for the control and prevention of bleeding episodes in patients with hemophilia. Other drug classifications granted included Orphan Drug Status and Breakthrough Therapy designation. 

FDA Approval Updates for Hemophilia Drugs

Two new hemophilia drug plant construction plans were initiated over the summer by separate manufacturers, headlines said.

In May, Bayer HealthCare broke ground in May on a $100 million product testing facility for hemophilia A drugs in Berkeley, California. The structure, which is replacing an existing older building, is estimated to be 80,000 square feet across three stories and should be completed in 2017. The company already makes and tests Kogenate FS, a German based company’s drug with sales of about $1.1 billion, according to 

In December, Bayer filed with the US Food and Drug Administration (FDA) for approval of its latest hemophilia experimental drug, the report continued. The drug, called Kovaltry, is a long acting hemophilia A treatment which would allow patients to be dosed once per week. If approved, the drug would be created and tested in the new Berkeley facility. Kovaltry and damoctocog, the drug, have been created in the facility for clinical trials.

The Danish company Novo Nordisk also announced plans to open a $225 million plant in Kalundborg by 2020. The structure would be about 80,000 square feet and house an additional 100 production and engineering employees to the 2,800 existing employees at the Kalungburg location.

Even though the company is known for specializing in diabetes drugs, they are expanding into the hemophilia drug market. The company will produce pharmaceutical drugs for NovoSeven — treatment for hemophilia A and B patients who form inhibitors – and future developments in hemophilia treatments. A newer version of the drug, called NovoEight, was approved in several countries in 2014 and is already available in Europe and Japan. The drug is expected to be available in the US in the fall.

“The investment in Kalundborg underscores our long term ambition to create and maintain jobs in Denmark,” Henrik Wulff, EVP of product supply, said in a 

. “This year alone we expect Novo Nordisk will create about 250 new jobs in Kalundborg.”

Novo is also developing longer acting treatments, the statement added. The company expected to add their long acting hemophilia A treatment candidate with the FDA in 2015, while another file expected for hemophilia A in 2018. Another project to aid the company’s production is to convert a biologics plant in New Hampshire they acquired from Japan’s Olympus Biologics, where they hired nearly 100 more employees.

Breaking Ground in Two Hemophilia Drug Construction Plants

Seven patients have been treated successfully for hemophilia B and so far essentially none have developed inhibitors, according to the results of phase I and II trials of Baxalta drug BAX 335.

The research was presented at the International Society on Thrombosis and Haemostasis Congress in Toronto, Canada in June. BAX 335 is an investigational factor IX (FIX) gene therapy treatment for hemophilia B designed to provide a mechanism for the patients’ own livers to produce FIX over an extended period of time following a single treatment dose.

The seven patients involved in the study were treated in three sequentially ascending dosing cohorts, and none of the patients were found to have developed inhibitors. The lowest cohort was treated with 2x1011 vector genomes [vg] per kilogram of body weight: vg/ kg and some FIX expression was observed in this group. The second group was treated with 1x1012 vg/ kg, and two patients experienced no bleeds without regular infusions of FIX. Additionally, one of these patients had sustained FIX expression levels of 20 to 25 percent for one year.

The third and highest dosing cohort was treated with 3x1012 vg/ kg and demonstrated expression levels at above 50 percent; however, two of these patients experienced an immune response which led to decreased FIX expression, the researchers said. One of those two patients resumed regular FIX infusions.

In previous studies, gene therapy technology has successfully managed immune responses. Additionally, throughout the study, immune responses were observed to maintain target trough levels.

“Gene therapy has the potential to achieve a long term therapeutic solution for people with hemophilia and will continue to be a key focus for Baxalta,” John Orloff, MD, vice president and global head of research and development at Baxalta, explained in a 

. “We continue to advance this program as we learn more about this new concept and its value for those living with hemophilia, with an opportunity to truly transform the treatment paradigm.”

Eventually, Baxalta hopes to modify the drug therapy so that only a single dose, administered intravenously, would be necessary. The company hopes another endpoint of the study can be to stabilize therapeutic plasma FIX activity, in addition to pharmacokinetics and immune response treatment. Additional patients are still being recruited to join the study.

Baxalta is also planning on examining the gene therapy technology for the treatment of hemophilia A, the statement concluded.

BAX 335 is Successful in Phase I and II Trials, Prevents Inhibitors

An analysis of randomized controlled trials (RCTs) 

 by the Institute for Quality and Efficiency in Health Care (IQWiG) determined that prophylactic treatment for hemophilia A is superior to on-demand treatment in some outcomes.

Researchers from the German Federal Ministry of Health identified 13 completed and three ongoing long term RCTs to help answer their three main research questions. IQWiG wanted to map the available evidence for long term, factor concentrate based treatments of patients with severe hemophilia A and B with respect to different treatment strategies, factor concentrates, dosing regiments, and prophylactic treatment regimens. The investigators wanted to compare the long term benefit of prophylactic and on demand treatments to the patient relevant outcomes in controlled prospective analyses. And thirdly, the investigators wanted to examine to what extent the current guidelines and treatments are based on the evidence.

Three hemophilia A studies were available for use to compare the benefit of prophylactic versus on demand factor concentrate based treatment (one done with adolescents and adults and two done with children). The data pointed to added benefits using prophylactic treatments for outcomes such as health status and pain, plus the success in severe bleeding outcomes. Looking specifically at children’s outcomes, there were no added benefits for either on demand or prophylactic strategies in relation to pain, joint function, or quality of life.

Only two of the studies included hemophilia B patients, the researchers said. The investigators were unable to draw any conclusions about prophylactic versus on demand factor concentrate based treatment for patients with hemophilia B.

The researchers wrote to German authorities on guidelines and treatment options and received 13 potentially relevant guidelines and four treatment algorithms. Only three turned out to be evidence based, the researchers found. However, most of the guidelines and algorithms did not contradict the findings from the benefit assessments. The researchers found that one of the guidelines recommended on demand treatment which was not supported by the evidence. Several recommendations that focused on preserving the functionality of joints were not supported by the available evidence, the researchers said, but only because there was no data available to be assessed from the studies.

“For the topics investigated on the basis of the identified studies on the treatment of hemophilia A and B, the degree of consistency between the underlying evidence in the guidelines and the corresponding evidence from the above studies was low, as the evidence base of the guidelines varied strongly or no evidence was provided,” the authors concluded. “Nevertheless, the guidelines and treatment algorithms do not generally contradict the results of the benefit assessment.”

An analysis of randomized controlled trials (RCTs) published by the Institute for Quality and Efficiency in Health Care (IQWiG) determined that prophylactic treatment for hemophilia A is superior to on demand treatment in some outcomes. 

December 2015

Well-Controlled Bleeding with rVIII-SingleChain

Two Grants Awarded to Medical College of Wisconsin Researcher

FDA Approval Updates for Hemophilia Drugs

Breaking Ground in Two Hemophilia Drug Construction Plants

BAX 335 is Successful in Phase I and II Trials, Prevents Inhibitors

Analysis of Hemophilia Studies Fit Guidelines and Recommendations

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