Concizumab is advancing into pediatric trials as an innovative, patient-friendly treatment for hemophilia patients, while additional alternatives to blood factor therapy are being developed.

Patients with hemophilia experiencing a traumatic or spontaneous bleed are typically infused with missing factors VIII or IX – a lifesaving therapy but one that imparts some risk of triggering inhibitors to the clotting factors.

This has led to a rash of interest in alternative approaches.

“Hemophilia care is in the midst of an enormous burst of innovation that started about a decade ago. This approach represents an extraordinary leap forward in our ability to offer our patients a more normal, less fearful life.”

Recently, a new monoclonal antibody has been introduced and is now nearing the end of the trial pipeline. The Novo Nordisk product, concizumab, uses an innovative mechanism to prophylactically protect against bleeding through subcutaneous injections.

Researchers for the Explorer7 trials demonstrated an 86 percent reduction in annual bleed rate for patients on concizumab prophylaxis in a typically recalcitrant population of patients aged 12 or older who have factor IX deficiency with inhibitors.

A pediatric trial, Explorer10, is now in phase 3, under the leadership of pediatric hematologist/oncologist Allison P. Wheeler, M.D., trial site investigator at the Hemostasis Treatment Clinic at Vanderbilt University Medical Center.

“Hemophilia care is in the midst of an enormous burst of innovation that started about a decade ago,” said Wheeler, who also serves as co-medical director of the coagulation laboratory. “This approach represents an extraordinary leap forward in our ability to offer our patients a more normal, less fearful life.”

Treatment Falls Short

Hemophilia is diagnosed in patients who are missing either factor VIII (hemophilia A) or factor IX (hemophilia B), two key coagulation pathway factors that contribute to the production of clot-building fibrin. Severe factor deficiency is defined as less than 1 percent of normal, valued at 100 percent; moderate is 1-5 percent; and mild is 6-45 percent.

“We’ve always given factor, mostly to those with severe disease or those with moderate disease who experience clinically severe bleeding,” Wheeler said. “Our original goal in factor replacement was to get the patient back up to 1 to 2 percent of normal factor levels, where they rarely, if ever, spontaneously bleed.”

The biggest downside of factor replenishment is that about a quarter of patients with hemophilia A develop factor inhibitors or antibodies. About 5 percent of those with hemophilia B react in a similar fashion. The reactions can be extremely severe and result in more complex and less effective therapy.

Patients who develop inhibitors may be given a factor VIII- or IX-bypassing agent, like recombinant activated factor 7 or FEIBA, when they bleed. Sometimes one of these is administered prophylactically. These agents act as a spark to initiate continuous coagulation, but the effectiveness is suboptimal, Wheeler says. The treatments are given by IV every few hours.

An alternative approach is to provide high doses of factor to tolerize patients with inhibitors, much the same way allergy shots work. However, she says this treatment is not always successful and, in hemophilia B, the excess factor IX can exit the intravascular space and cause complications like nephrotic syndrome.

21st Century Therapies

Wheeler says the therapeutic innovations are taking place in three realms: gene therapy, factor VIII mimetics, and rebalancing agents.

Two gene-therapy drugs have been approved, but consistent with other applications, the cost of gene therapy renders it inaccessible to a broad patient population.

Factor VIII mimetics are synthetic drugs – monoclonal antibodies – that mimic the effect of the natural proteins. One factor VII mimetic is already on the market and one in the clinical trial pipeline, but none that mimic factor IX.

“The drug is not as effective as factor VIII itself, but it works well and prophylactically as a steady-state drug given by subcutaneous injection,” Wheeler said. “Still, patients may develop inhibitors to mimetics in the same way they do with factor VIII itself.”

Inhibiting the Inhibitor

Concizumab, one of the three new drugs in the rebalancing class, is conceived on a novel inversion of the standard procoagulant approach. Rather than raising levels of procoagulants by compensating for the missing factor, these drugs establish hemostasis by lowering the natural anticoagulant factors (TFPI or antithrombin) in the blood.

Concizumab prevents the coagulation-inhibitor TFPI from inhibiting prothrombotic factor Xa (Fxa) and the TF/FVIIa complex, allowing for balance between procoagulant and anticoagulant levels in the blood at lower levels. Marstacimab is a second anti-TFPI molecule, and fitusiran works in a similar way, inhibiting antithrombin.

These rebalancing agents work to solve the three challenges we face in treatment,” Wheeler said. “They aren’t factor, so inhibitor development has less clinical impact; they are given subcutaneously, not by IV; and they provide prophylaxis even in the presence of a factor inhibitor because they bypass the factor VIII-factor IV system.”

Historically, she has provided concizumab to pediatric patients on a compassionate-use basis and has plans to enroll future patients in the phase 3 pediatric trial (Explorer 10) now in progress.


Allison P. Wheeler, M.D.

Allison P. Wheeler, M.D., M.S.C.I., is an associate professor of pediatrics and pathology, microbiology and immunology, and director of research for benign hematology at Vanderbilt University Medical Center. Her research is primarily focused on hemostatic disorders in pediatric patients, with a specific focus in women with bleeding disorders.