Emicizumab Replaces Factor VIII Function in Hemophilia A

Daniel M Keller, PhD

July 11, 2017

BERLIN, GERMANY — Once-weekly subcutaneous administration of emicizumab (Roche) as prophylaxis reduced or prevented bleeds in people with hemophilia A and inhibitors to factor VIII. More than half of the patients experienced no bleeds during the course of the HAVEN 1 trial[1].

Speaking here at the International Society on Thrombosis and Haemostasis 2017 Congress, Dr Johannes Oldenburg (Institute of Experimental Hematology and Transfusion Medicine, University Clinic Bonn, Germany), president of the society, described this novel approach using emicizumab, a bispecific monoclonal antibody that bridges activated factor IX and factor X and thereby replaces the missing factor VIII.

Emicizumab prophylaxis was "associated with a significantly lower rate of bleeding events than no prophylaxis or previous prophylactic treatment with bypassing agents among patients with hemophilia A with inhibitors, and it improved health-related quality of life," Oldenburg and colleagues conclude in their report, also published simultaneously online July 10, 2017 in the New England Journal of Medicine.

The agent was safe when given alone or with recombinant factor VIIa, they write. Thrombotic microangiopathy or thrombosis occurred only in those who received high cumulative doses of activated prothrombin complex (aPCC) concentrate for breakthrough bleeding while receiving emicizumab prophylaxis; "thus, the usefulness of this bypassing agent may be limited in patients who have bleeding events while receiving emicizumab prophylaxis," they note.

"Emicizumab may provide a weekly, subcutaneous, prophylactic therapeutic option for patients with hemophilia A with inhibitors," the authors conclude.

Neutralizing Antibodies

About 30% of patients with hemophilia A develop neutralizing antibodies ("inhibitors") to factor VIII, rendering it ineffective. Because emicizumab does not share homology with factor VIII, the inhibitors have no neutralizing effect on it.

The open-label HAVEN 1 trial enrolled people 12 years of age or older with factor VIII inhibitors. Oldenburg presented results for 53 participants who had previously received episodic factor VIII bypassing agents (BPAs). They were randomly assigned 2:1 to emicizumab (group A; n=35) or to no prophylaxis (group B; n=18).

Groups A and B had mean ages of 38 and 35.5 years, respectively (overall range 12–68 years). About 70% of people in each group had nine or more bleeds in the 6 months prior to study entry. There was a wide range of inhibitor titers in each group, ranging from 5 to 1570 Bethesda units (BU) in group A and 18 to 4500 BU in group B.

Over 24 weeks, 62.9% of patients in group A receiving emicizumab had no bleeds, the primary end point of the trial, compared with only 5.6% of those people not receiving the drug. On prophylaxis, 85.8% had zero to three bleeds vs 11.2% without prophylaxis.

There was an 87% reduction in the annualized bleeding rate between the groups—2.9 bleeds/year (95% CI 1.69–5.02) with prophylaxis vs 23.3 bleeds/year (95% CI 12.33–43.89) without prophylactic emicizumab (P<0.0001).

After 24 weeks, all participants received emicizumab. Oldenburg noted that to date, none has discontinued the drug for lack of efficacy, and "none of these patients tested positive for antidrug antibodies."

A secondary end point was the reduction in all bleeds and in specific types of bleeds. Compared with no emicizumab, emicizumab prophylaxis reduced the annual rate for all bleeds (80%), treated spontaneous bleeds (92%), treated joint bleeds (89%), and treated target joint bleeds (95%) (all P≤0.005).

In a comparison of emicizumab prophylaxis vs prior BPA prophylaxis within individual patients, emicizumab produced a 79% reduction in the annualized bleed rate: 70.8% had no bleeds when on emicizumab, compared with only 12.5% when on prior BPA prophylaxis (P=0.0003). This was a "statistically significant, clinically meaningful reduction in bleed rates with emicizumab prophylaxis vs prior BPA prophylaxis," Oldenburg said.

Emicizumab prophylaxis was associated with statistically significant and clinically meaningful improvement in health-related quality of life and physical health scores.

The drug was safe and well tolerated, as shown by an expanded cohort of patients that included groups A and B (n=103). Seventy-three patients experienced at least one adverse event (AE), of which 23 were gauged to be trial-related, and nine had a serious AE, including one death from a rectal hemorrhage. Grade 3 or greater AEs occurred in eight patients. About 15% of patients had injection-site reactions.

From an assessment of the interaction of emicizumab and aPCC, the researchers saw thrombotic microangiopathy or thrombotic events only with aPCC treatments averaging greater than 100 U/kg daily for 24 hours or more. They recommended that aPCC be avoided if possible, and if not, that lower doses be used and with caution.

"Results represent a potential paradigm shift and new standard of care for treatment of hemophilia A with inhibitors, with an effective weekly subcutaneous, prophylactic therapeutic option," Oldenburg said. Data from the trial have been submitted to the US Food and Drug Administration and to the European Medicines Agency.

One sticking point, as reported by FierceBiotech and others, is that Shire obtained a preliminary injunction from a court in Hamburg, Germany, over the weekend to keep Roche, the developer of emicizumab, from making what Shire considers inaccurate and misleading statements—that is, ascribing the blame for adverse blood-clotting events to Shire's aPCC product, FEIBA, when used at high doses in combination with emicizumab. They are both competing for a share of the approximately $11-billion/year hemophilia market.

Shire also objected to Roche using "treated bleeds" as the primary end point of the trial and scoring a success by Roche's measure, whereas ClinicalTrials.gov lists "number of bleeds over time" as the primary end point.

Extraordinary Times

In an editorial accompanying publication of HAVEN 1[1], Dr David Lillicrap (Queen's University, Kingston, ON) calls these results "extremely important for the hemophilia treatment community, which has battled the hemostatic calamity of factor VIII inhibitor formation with the same bypassing therapies for the past 30 years.

"Although the preferred treatment of the infrequent events of breakthrough bleeding during the administration of emicizumab is not clear, it is obvious that repeated high doses of activated prothrombin complex concentrate should be avoided," he writes. "Similarly, how emicizumab prophylaxis will be integrated with current schedules for the induction of immune tolerance to factor VIII remains to be evaluated."

In the meantime, he notes, "weekly subcutaneous emicizumab prophylaxis appears to offer a marked reduction in bleeding rates and improvement in quality of life for this very challenging patient group."

Additional studies are already in progress examining the benefit of emicizumab prophylaxis in pediatric patients with hemophilia with inhibitors, and a study involving patients with hemophilia A without inhibitors is planned, he points out.

"These are extraordinary times for innovation in hemophilia therapy, and the introduction of emicizumab represents a major contribution toward achieving an enhanced standard of care for this lifelong bleeding disorder," Lillicrap concludes.  

Dr Wolfram Ruf (Johannes Gutenberg University, Mainz, Germany), commented to theheart.org|Medscape Cardiology that emicizumab represents "a very exciting new area where a bypassing agent on a new therapeutic principle showed a marked reduction in bleeding events.

"I think there was really a major effect on reducing the bleeding in the hemophilic patients with inhibitors to factor VIII," Dr Ruf noted. He said he believes it is "certainly a game changer in the long run that a new principle can be brought into the hemophilia therapy."

Factor VIII replacement therapies and gene therapies to produce factor VIII are aimed at replacing the natural molecule. "Here you actually have an engineered molecule that is completely an antibody, that is unrelated to factor VIII, but it does the function of factor VIII," he said. "I think that's the novelty, and it's nice to see ideas like that actually move into the clinic with success."

A goal would be to eliminate factor VIII inhibitors from patients, but if that could be achieved, Ruf said clinical trials would have to be done to see where emicizumab then fits in—whether to go back to using factor VIII or to stick with emicizumab.

The study was funded by F Hoffman–La Roche and Chugai Pharmaceutical. Oldenburg received grants and personal fees and served as member of a board of directors or advisory committee for Baxter, Bayer, Biogen Idec, Biotest, Chugai, CSL Behring, Grifols, Novo Nordisk, Octapharma, Pfizer, Roche, Shire, and Sobi. Disclosures for the coauthors are listed on the journal website. Lillicrap discloses grant support from Bayer, Bioverativ, CSL Behring, and Octapharma outside the submitted work. Ruf had no relevant financial relationships.

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