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Hemophilia drug interferes with APTT-based assays

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Anne Paxton

September 2018—When a miracle drug comes along that is predicted to cause havoc in the laboratory, the drug could well seem like a double-edged sword. In the case of emicizumab (Genentech’s Hemlibra), for patients with hemophilia A, the mix of both benefits and drawbacks is likely to settle in for the long term.

Laboratories adjusting to the widening rollout of emicizumab will need to keep an important consideration in mind when performing coagulation testing for hemophilia patients, says Dorothy M. Adcock, MD, chief medical officer of LabCorp Diagnostics. “Emicizumab can interfere in APTT-based assays. The traditional factor VIII activity assay, the APTT-based one-stage assay, is not an accurate measure of patients’ level of hemostasis when they are on emicizumab.”

Dr. Levy

Emicizumab is a monoclonal antibody that represents one of the most dramatic advances in hemophilia treatment in decades. Approved by the FDA in November 2017, emicizumab could significantly reduce the treatment and disease burden of thousands of hemophilia A patients who have antibodies in their blood, known as inhibitors, that render standard factor VIII replacement therapies ineffective. Very soon, coagulation experts believe, the benefits of emicizumab will extend to all hemophilia patients.

“For patients with inhibitors, emicizumab is almost revolutionary in that they really haven’t had effective therapies to prevent bleeding,” says Guy A. Young, MD, director of the Hemostasis and Thrombosis Center at Children’s Hospital Los Angeles. He notes that patients with inhibitors have a 70 percent higher mortality rate than hemophilia patients without inhibitors. “In addition, those patients had a tremendous treatment burden—IV infusions three or four times a week or every day, with treatments lasting 45 minutes to an hour.” As a result, many did not adhere to the treatment. With emicizumab, patients with inhibitors will have less burdensome therapies that still lower their bleeding rates to those of patients without inhibitors who are on prophylactics, Dr. Young says.
“Bringing this medicine to patients is one of the things I am most proud of in my career,” Gallia Levy, MD, PhD, global clinical development lead for Hemlibra at Genentech, wrote in an email to CAP TODAY.

However, the benefits of emicizumab may come at the cost of laboratories’ ability to produce accurate coagulation test results for hemophilia A patients because emicizumab behaves differently from factor VIII in a key way: “Even the slightest concentration of emicizumab in the blood will normalize the activated partial thromboplastin time,” Dr. Young points out.

This means that activated partial thromboplastin time or any APTT-based test cannot be used in patients taking the drug, he says. “We will not be able to measure factor VIII levels accurately with the assays most available in the U.S. For the inhibitor patients, we will also not be able to track their inhibitor levels with the traditional assay. We may have a patient on emicizumab that is working fantastically to prevent their bleeding. That part’s great. But how we are going to be able to measure factor VIII activity and inhibitor titers is problematic currently.”

“That’s how emicizumab is going to create havoc in the laboratory, because lab tests that we normally would be comfortable doing and interpreting in hemophilia suddenly are no longer going to be accurate.”

While Genentech’s current U.S. product label outlines how emicizumab interacts with different coagulation tests and offers guidance on which tests are unaffected by the drug, coagulation testing experts interviewed by CAP TODAY point out there remains a critical awareness gap about the pitfalls of testing emicizumab patients.

Emicizumab reduces the bleed rate in hemophilia A patients with inhibitors via a simplified prophylaxis regimen that is patient-friendly: self-administered subcutaneous infusions once a week. In clinical trials of emicizumab, the drug produced a stunning difference in these patients’ bleeding levels. For instance, 54 of 57 patients (94.7 percent) under age 12 who received weekly subcutaneous emicizumab doses for bleeding prophylaxis had zero treated bleeds, in contrast with the typical pattern for these patients of monthly bleeds.

Personal stories have underscored the effect of emicizumab on hemophilia patients’ quality of life. “I know of one eight-year-old boy with factor VIII inhibitors who is very proud that he can administer his Hemlibra himself,” Dr. Levy says. Before Hemlibra, the boy needed infusions that could take up to two hours at least three times a week. The half-life of infused factor VIII is only 10 to 12 hours. Another pediatric patient cited by Roche, a co-developer of emicizumab, had experienced scores of debilitating ankle bleeds, but those bleeds stopped once he began receiving emicizumab during clinical trials.

Emicizumab was made possible by scientists at Chugai Pharmaceutical who had an idea, completely novel in 2000, of using a bispecific antibody to replace the function of factor VIII and help restore the blood clotting process, Dr. Levy says. “The scientists were already working on advances in antibody engineering and saw an opportunity to apply this approach to hemophilia A.”

The research leading to emicizumab entailed an extended, needle-in-a-haystack search. “Finding an antibody with the right configuration and properties to mimic factor VIII’s biological activity required screening more than 40,000 antibodies and took nearly 10 years. The molecule that would become Hemlibra was selected as the candidate for clinical trials in 2010,” Dr. Levy says. But all that effort led to a landmark in drug development: “Hemlibra is the first antibody medicine ever developed that replaces the function of a missing or altered protein.”

The clinical development of the drug was done as a partnership between Genentech, Chugai, and Roche (all members of the Roche Group). At the clinical trial phase, Genentech and Roche first studied how people with hemophilia A managed bleeds with their previous treatment options by gathering data in a noninterventional study. “Some of the people in this study went on to enroll in our pivotal studies of Hemlibra, allowing for a first-of-its-kind intrapatient analysis, the first time two prophylactic treatments have been compared prospectively in the same person in a hemophilia study,” Dr. Levy says. So the Hemlibra clinical trial program not only has had an impact on lives of people with hemophilia A but also may help influence the way hemophilia clinical trials are designed in the future, she points out. “In addition, a pivotal clinical trial, HAVEN 1, showed statistically significant results for 13 different bleed-related endpoints.”

Hemophilia A patients’ development of antibodies (inhibitors) to factor VIII replacement products is one of the most serious and common adverse events in hemophilia treatment, says Dr. Adcock. “Development of inhibitors occurs in about 33 percent of patients with severe factor VIII deficiency who receive replacement therapy. Once patients develop antibodies, it can be very difficult to treat them and very expensive. The cost of treating patients with factor VIII inhibitors is upwards of $1.5 million per year or more.”

Dr. Adcock

Patients receive factor VIII infusions as a prophylactic measure to prevent spontaneous bleeding or bleeding associated with trauma or everyday activities. But this therapy requires time-consuming intravenous treatment and, despite therapy, patients often experience bleeding into the joints, which can cause disabling arthritis. “The whole social impact is much broader than the cost of the drug,” Dr. Adcock says.

Until emicizumab’s entrance on the scene, clinicians had few effective recourses for patients who develop antibodies to factor VIII, Dr. Adcock notes. “Clinical protocols to treat these patients and to reverse the inhibitor response are not always effective, and they are very costly. One approach to eradicate the inhibitor is immune tolerance induction, where high doses of the replacement factor are administered on a frequent basis. The mechanism by which this may be effective in inhibitor eradication is not known.”

With emicizumab, the cost of treating patients with inhibitors could decline. In April, the nonprofit Institute for Clinical and Economic Review (ICER) released a final evidence report on emicizumab, which evaluated how emicizumab could improve health while lowering costs for certain people with hemophilia. The report concludes, “In assessing the value of treatments for hemophilia, payers should be aware of important benefits and contextual considerations that are not typically captured in cost-effectiveness analyses.”

“So even though emicizumab is expensive—about $430,000 per year—it still may be cost-effective in certain populations,” Dr. Adcock says. The report makes the case that third-party payers should cover emicizumab because, over time, it will reduce treatment costs. But the ICER report also warns that some controls on the price may be needed: “Given that emicizumab may gain indications for broader use, indication-specific pricing will likely be essential to tailor the price to reflect the clinical and economic value of the drug in different patient populations.”

Emicizumab works by replacing or mimicking the function of the missing cofactor, activated factor VIII, says Stefan Tiefenbacher, PhD, vice president of LabCorp and technical director of Colorado Coagulation, a member of the LabCorp Specialty Testing Group. “Emicizumab bridges factor IXa and factor X, bringing them into proper alignment—which is normally the function of activated factor VIII. However, there is a big difference between factor VIII and this bispecific antibody: Unlike factor VIII, which is highly regulated, emicizumab, once administered, does not require activation and circulates in the patient in its active form until it is cleared from circulation.”

Dr. Tiefenbacher

At the 2018 Scientific and Standardization Committee meeting of the International Society on Thrombosis and Haemostasis, Dr. Tiefenbacher, who develops drug-specific assays for clinical trials, presented a special session on practical considerations, including laboratory issues, that emicizumab raises.

This bispecific antibody has a long half-life of 28 days, he explains. “With more conventional hemophilia factor VIII replacement treatments, the ‘wash-out’ period of the factor product is usually a few days, maybe a week for the newer extended half-life products. Thus, you can safely perform a factor VIII inhibitor assay after a few days of wash-out without having to be concerned about the factor VIII replacement product interfering in the assay.” If, on the other hand, a hemophilia A patient is treated with emicizumab, the bispecific antibody circulates in the patient’s blood for up to six months after the last treatment, creating significant challenges in the laboratory when APTT-based factor activity and inhibitor are ordered, he says.

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