The emergence of emicizumab (Hemlibra) has marked a sea change in both the clinical management and laboratory monitoring of many individuals with hemophilia A.

This drug—first introduced in 2017 as an alternative to bypass agents for patients who have developed inhibitors to and can no longer take standard Factor VIII (FVIII) replacement therapy—also is increasingly being used in patients without FVIII inhibitors. Several considerations are driving this uptick: emicizumab’s ease of use and less frequent dosing, as well as data supporting its efficacy.

Instead of replacing the clotting agent FVIII, emicizumab mimics its activity using a bispecific monoclonal antibody, said Michael Spannagl, MD, PhD, professor in the department of hemostasis at Ludwig Maximilian University of Munich in Germany. This creates a steady level of the drug for weeks, eliminating the need for frequent dosing and monitoring associated with FVIII replacement, which has a short half-life resulting in between-dose peaks and troughs in blood levels.

“It’s a completely new concept and completely different pharmacology,” added Spannagl.

To support the clinical management of patients taking emicizumab, the National Hemophilia Foundation (NHF) and the United Kingdom Haemophilia Centre Doctors’ Organisation (UKHCDO) have each created a guideline. Both guidelines and the drug’s manufacturer, Genentech, recommend against using traditional laboratory tests based on activated partial thromboplastin time (aPTT) because they will give aberrant results. Instead, all three recommend using specific chromogenic assays as well as other adjustments in testing protocols.

Expanding Use and Indications

Impressive results from the HAVEN 2 trial published in late 2019 showed that emicizumab dramatically reduced bleeds in children with hemophilia A who have developed inhibitors to FVIII replacement therapy (Blood 2019;134:2127–38). These results further established the role of emicizumab, which was first approved by the Food and Drug Administration (FDA) in 2017 for adults and children with hemophilia A with FVIII inhibitors, said Steven Pipe, MD, pediatric medical director of the Hemophilia and Coagulation Disorders Program at the University of Michigan in Ann Arbor.

“It’s really a slam dunk as far as patients with inhibitors go,” added Pipe, who is also director of the university’s special coagulation laboratory. “[Emicizumab] has changed the standard approach for patients with FVIII inhibitors. In my own practice there are no patients with inhibitors who are not on emicizumab for their regular prophylaxis.”

Before emicizumab became available, Pipe explained, the only prophylaxis options for patients with inhibitors to FVIII were bypassing agents, such as recombinant factor VIIa or activated prothrombin complex concentrate. These products have inconsistent results for treating bleeds and don’t prevent bleeds as effectively as FVIII, he said. Emicizumab, however, has “phenomenal results with patients getting their bleed rates essentially down to zero,” Pipe said.

Spannagl agreed that emicizumab represents a great improvement for patients, noting that bypassing agents are very expensive and pose safety concerns.

Pipe expects that up to 90% of individuals with inhibitors eventually will use emicizumab. A growing number of patients without inhibitors also have started taking the drug since FDA approved this indication in 2018. However, Pipe noted, not all are eager to switch from FVIII therapy, which has been the standard-of-care for decades.

“This patient population is generally conservative, particularly with respect to safety issues with new products,” he explained. “So, if a patient is well-managed with regular prophylactic therapy with FVIII, they might not have embraced a transition to emicizumab.”

Still, Pipe has seen benefits in patients who have made the switch. For example, he noted that emicizumab’s subcutaneous administration weekly, every 2 weeks, or every 4 weeks, improves adherence. The drug’s very long half-life means patients who forget a dose can take it as soon as they remember without fear of a breakthrough bleed beforehand, he added.

“What I appreciate most about emicizumab prophylaxis is that it provides steady state hemostatic protection, as opposed to the peaks and troughs of traditional FVIII replacement therapy,” he said. Additionally, he said it might benefit individuals who have bleeding in their joints even just once or twice a year, which can lead to damage over time.

Despite these advantages, emicizumab does not completely normalize clotting, Pipe noted, and some patients will have breakthrough bleeds that require FVIII replacement, though often just a single dose. In addition, FVIII replacement lends itself better for customizing to patients’ needs.

“Overall, at least half of our non-inhibitor patients use emicizumab for prophylaxis at this point, and that number is growing,” Pipe noted.

Less Monitoring, Different Assays

As growing numbers of individuals with hemophilia A take emicizumab, all laboratorians should be aware that traditional, clot-based FVIII assays will overestimate factor FVIII activity. For example, one of these tests used on a patient taking emicizumab might yield FVIII concentrations in the 500% to 900% range above normal, said Neil Harris, MD, core laboratory director at the University of Florida in Gainesville.

This can be a serious problem if someone with hemophilia A who is taking emicizumab presents at emergency and a clinician concludes the patient doesn’t need FVIII based on such an aberrantly high reading on a standard clot-based assay, said Pipe, who chairs the NHF Medical and Scientific Advisory Council that drafted the guideline. To prevent this, he educates his patients and their parents to tell emergency physicians to not rely on standard clot-based assays.

Routine prophylactic dosing of emicizumab doesn’t require monitoring because the drug’s levels remain stable, Spannagl said, but a different set of tests and reagents is needed perioperatively and in emergency situations.

“You have to develop a completely different laboratory management system for patients with hemophilia on emicizumab,” he said. For example, Vince Jenkins, PhD, laboratory head of specialized hemostasis diagnosis and research at University Hospital of Wales in Cardiff, said he and his colleagues set up an electronic health record notification, accessible to any clinician in Wales, that will alert laboratorians that a patient has hemophilia and is being treated with emicizumab, which will interfere with aPTT test results.

“The important thing is that the shortened aPTT in patients treated with emicizumab does not reflect the hemostatic state,” said Jenkins, who was also the lead author of the UKHCDO guideline.

Instead of one-stage clot-based aPTT assays, both NHF and UKHCDO recommend chromogenic assays using bovine reagents to measure FVIII activity. This might be necessary when a patient requires FVIII replacement because of a bleed or surgery. Harris explained that the chromogenic substrate assay test uses an enzymatic reaction rather than the one-stage clot-based aPTT assay. With bovine reagents, the reaction won’t recognize the endogenous human clotting factors, the activity of which is driven by the presence of emicizumab, thus providing a more accurate reading of true FVIII activity.

However, these tests aren’t widely available in the U.S., said Olajumoke Oladipo, MD, DABCC, director of coagulation and hematology and associate director of the automated testing laboratory at Penn State Health Milton S. Hershey Medical Center in Hershey, Pennsylvania.

A recent College of American Pathologists’ (CAP) survey found that only 25 laboratories were participating in CAP’s chromogenic FVIII activity proficiency testing, she noted, compared with more than 300 that perform traditional, one-stage clot-based FVIII assays.

Jenkins stressed that the former require a high level of technical capacity and are unlikely to be done outside of specialty centers. The chromogenic Bethesda assay for measuring inhibitors is also not widely available in the U.S., added Oladipo.

“It’s absolutely critical that people are aware that they need to send inhibitor patient assays to a lab that is capable of evaluating patients taking emicizumab,” Pipe said. In the U.S., both hemophilia treatment centers and the Centers for Disease Control and Prevention have this capability.

Oladipo said that at her institution, emergencies or other circumstances calling for STAT chromogenic FVIII activity levels are uncommon. “We do send our samples out to reference labs when needed, which is very rare,” she said. “There’s really no urgent push to have all these tests in-house because the drugs have a long half-life of about 4 weeks and maintain a steady level in the system for a long time.”

Jenkins suggested that laboratorians familiarize themselves with emicizumab’s mechanism of action and collaborate closely with clinicians who prescribe the drug. “There needs to be good communication between the treating physician, the hemophilia physician, and the laboratory,” he stressed.

The NHF guideline notes that in rare circumstances individuals develop anti-drug antibodies to emicizumab. In the HAVEN 2 trial, two of 88 children taking emicizumab developed antibodies, and the drug lost efficacy in one of them.

“The incidence [of anti-drug antibodies] appears to be less than 1% of patients who are treated, but it is possible that they would have neutralizing potential and then wipe out the protective effect of emicizumab,” said Pipe.

Spannagl noted that anti-drug antibodies have been identified as a concern in the fields of rheumatology and oncology, which use dozens of therapeutic antibodies. However, he believes there is less risk of anti-drug antibodies with fully humanized antibodies like those used in emicizumab.

“We are hopeful that they will not develop in many patients, but we have to be aware that one patient or another might develop antibodies against emicizumab,” he said.

If loss of efficacy is suspected because of breakthrough bleeding, a chromogenic assay with human reagents or a widely available conventional aPTT assay could be used, the NHF guideline notes. The aPTT test should be in the normal range for a patient taking emicizumab and clot-based assays will be well above normal, so a prolonged aPTT assay result or low FVIII concentration on a clot-based test might provide a preliminary warning of drug failure, the guideline notes. “Routine assays available in any hospital laboratory are able to provide that initial assessment,” Pipe said.

The UKHCDO recommends against using aPTT as a surrogate to measure emicizumab efficacy, because even low levels of emicizumab might interfere with the result, Jenkins explained. “You might get a normal aPTT even with low levels of the drug,” he explained. Instead, this guideline recommends a one-stage clotting assay with emicizumab-specific calibrators to measure emicizumab levels. The emicizumab-specific calibrators available in the U.K., however, are only available in the U.S. for research use, according to Narayanan Ramamurthy, director of research and development at r2 Diagnostics, the company that makes them.

Oladipo agreed that the aPTT assay is sensitive enough to detect rare cases of loss of emicizumab efficacy. “Prolongation of the aPTT really is an indication that the drug is not effective, especially if you know the baseline for the patient,” she said. “The aPTT is a test that is readily available, it’s affordable, and it’s in almost every lab.”

As laboratories adapt to the challenge of monitoring patients taking emicizumab, they should also be aware that other non-FVIII replacement therapies are in the pipeline, Pipe said. For example, he noted drugs that target the coagulation inhibitor antithrombin, tissue factor pathway inhibitor, and activated protein C. He added, “this is going to continue to challenge laboratories that support patients taking these nontraditional hemophilia therapies.”


Pipe has received consulting fees from ApcinteX, Bayer, BioMarin, Catalyst Biosciences, CSL Behring, HEMA Biologics, Freeline, Novo Nordisk, Pfizer, Roche/Genentech, Sangamo Therapeutics, Sanofi, Takeda, Spark Therapeutics, and uniQure. Jenkins has received a consultancy fee from Roche/Chugai. Oladipo, Harris, and Spannagl report no disclosures.

Bridget M. Kuehn is a science writer in Chicago, Illinois. +Email: [email protected]