Clinicians Test New Strategies for Hemophilia Treatment

Kate M. O'Rourke


March 13, 2015

The management of hemophilia has come a long way, with researchers continuing to make strides against this disorder. Recently, Medscape asked hemophilia experts to weigh in on noteworthy news from the past 6 months.

Hemophilia A and B are congenital bleeding disorders caused by insufficient thrombin generation. Hemophilia A is due to a deficiency in factor VIII; hemophilia B is due to a deficiency in factor IX. In the presence of normal levels of endogenous anticoagulants, deficiency of factor VIII or IX results in an imbalance of the hemostatic system toward a bleeding phenotype.

Within the past year, two long-lasting factor replacement products have come on the market. Eloctate® is the first long-lasting recombinant factor VIII Fc fusion protein therapy for hemophilia A, cutting the frequency of prophylactic infusions to every 3-5 days. Alprolix® is the first long-acting recombinant coagulation factor IX Fc fusion protein for hemophilia B.

Several others long-lasting factor products are in the drug development pipeline, according to Miguel Escobar, MD, a hemophilia expert at the University of Texas Health Science Center at Houston. These include nonacog beta pegol (N9-GP) and rFIX-FP (fusion protein linking recombinant coagulation factor IX), both for hemophilia B.[1,2] The US Food and Drug Adminstration (FDA) is currently reviewing data on rFIX-FP and is expected to make a decision on approval soon.

On another front, in October the FDA approved Obizur™ (antihemophilic factor [recombinant], porcine sequence) for the treatment of acquired hemophilia. Because the product is recombinant, patients do not need to worry about the transmission of porcine pathogens, which was a concern with a previous product that was pulled from the market, said Dr Escobar. The other drugs approved for acquired hemophilia A are bypassing agents, and it is thus difficult to monitor their efficacy.

"With this new recombinant porcine product, clinicians can monitor factor VIII levels and assess efficacy," said Dr Escobar. On the downside, patients can potentially develop an antibody (inhibitor) against the drug. "Another downside is that you have to use a large volume, but this product is a good option to have," Dr Escobar said. "We just need more experience with it." He noted that acquired hemophilia A is rare.

Dr Escobar said that researchers are also making strides with gene therapy, with several gene therapy trials in hemophilia currently ongoing. In November, researchers reported that in 10 patients with severe hemophilia B, an infusion of a single dose of AAV8 vector resulted in long-term therapeutic factor IX expression that was associated with clinical improvement.[3] There was a dose-dependent increase in circulating factor IX to a level that was 1%-6% of the normal value over a median period of 3.2 years. In the high-dose group, a consistent increase in the factor IX level to an average of 5.1% in all six patients resulted in a reduction of more than 90% in both bleeding episodes and the use of prophylactic factor IX concentrate.

A transient increase in alanine aminotransferase occurred in the high-dose group, but this resolved over a median of 5 days after prednisolone treatment. No late toxic effects from the therapy have been reported. 

"This is a very important study and will be a big, big winner if patients continue to make factor IX," said Dr Escobar. "The fact that they are continuing to do so at roughly 3.5 years is great."

According to Christopher Walsh, MD, PhD, director of the Hemophilia Program at Mount Sinai School of Medicine, New York, a hot area of hemophilia research is factor mimetics. In December, researchers presented results from a phase 1/2 trial of ACE910, a first-in-class factor mimetic.[4]

ACE910 is a humanized bispecific monoclonal antibody engineered to simultaneously bind factors IXa and X, thereby mimicking the factor VIII cofactor function in hemophilia. "ACE910 mimics the function of the protein without being a factor," said Dr Walsh.

ACE910 was tested in 18 patients with severe hemophilia A, some of whom had inhibitors. After 12 weeks of treatment, once-weekly subcutaneous administration of ACE910 was well tolerated and significantly reduced the annualized bleeding rate during treatment, compared with the rate seen in the 6-month period before study enrollment. All patients with prior bleeding events experienced reductions in their annualized bleeding rate, with the rate of reduction reaching 100% for patients in each of the three cohorts (Table). The drug was effective in patients with inhibitors, and no patient developed an inhibitor to ACE910.

Table. Efficacy of ACE910 in Patients With Severe Hemophilia A

Treatment Arm Patients Annualized Bleeding Rate
Cohort 1 (n = 6)
0.3 mg/kg ACE910
2 without inhibitors
4 with FVIII inhibitors
22%-100% reduction
64.7%-100% reduction
Cohort 2 (n = 6)
1 mg/kg ACE910
2 without inhibitors
4 with FVIII inhibitors
100% reduction
88.9%-100% reduction
Cohort 3 (n = 6)
3 mg/kg ACE910
3 without inhibitors
3 with FVIII inhibitors
0%a-100% reduction
100% reduction

FVIII = factor VIII

aOne patient did not report bleeding episodes at baseline or during the study.

According to Dr Walsh, ACE910 is important for several reasons. "You have a drug that doesn't cause an inhibitor, according to what they have seen; it seems to be equivalent to factor VIII; and it can be given subcutaneously and at a fairly long interval," he said.

Researchers are also aiming efforts at blocking tissue factor pathway inhibitor (TFPI) and antithrombin III (AT-III). The anticoagulant process is governed by four main plasma proteins: AT-III, TFPI, protein C, and protein S. These four proteins act as the brakes on the clotting system. "What several groups are doing is trying to take the brakes off the clotting system in the setting of not having either factor VIII or factor IX," said Dr Walsh.

In December, researchers reported interim results from a phase 1 trial of a subcutaneously administered RNA interference therapeutic called ALN-AT3 in healthy volunteers and patients with hemophilia A or B.[5] The drug aims to reduce levels of AT-III, thus increasing thrombin generation and restoring hemostatic balance in patients with hemophilia.

The study included both healthy volunteers and individuals with severe or moderate hemophilia A or B. With the single ascending dose study in healthy volunteers completed, the multiple ascending dose study in patients with hemophilia is ongoing. Subcutaneous administration of ALN-AT3 once weekly for 3 weeks at low doses of 15g/kg (n = 3) or 45g/kg (n = 1) resulted in as much as a 57% knockdown of antithrombin. The effects of ALN-AT3 lasted for about 60 days after a single dose, and the drug was well tolerated. All adverse events were mild, and four out of five adverse events were thought to be unrelated to the study drug. There were no injection-site reactions or laboratory abnormalities.

"The patients didn't have any bleeding, and this drug has a really long half-life," said Dr Walsh. He noted that the applicability to persons with hemophilia who have inhibitors makes the drug a particularly appealing approach.

Multiple companies are testing inhibitors of TFPI. "They are using different schemes—monoclonal antibodies in some settings, fusion peptides, binding antibodies, and aptamers," he said. Researchers have developed and validated robust immunoassays for the measurement of plasma and platelet TFPI.[6] In vitro experiments presented in December show that a TFPI inhibitor composed of two TFPI antagonistic peptides completely inhibits TFPI.[7]

In a study published in January, the anti-TFPI antibody concizumab was tested in 28 healthy volunteers and 24 patients with hemophilia.[8] Concizumab had a favorable safety profile after single intravenous or subcutaneous administration. The researchers identified a concentration-dependent procoagulant effect, supporting further study. It will be several years before these attack strategies can be thoroughly vetted.


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