Emicizumab 'Life-Changing' for Hemophilia A With Inhibitors

ATLANTA — Emicizumab (Hemlibra, Roche), recently approved to prevent or reduce the frequency of bleeding episodes in children and adults with hemophilia A with factor VIII inhibitors, has been hailed by experts as a "game changer" for this patient population.

Now details from an updated analysis from HAVEN 2, the largest phase 3 study reported in pediatric patients with hemophilia A with inhibitors to factor VIII, show that the drug was effective in substantially reducing bleeds and was well tolerated.

"Weekly subcutaneous emicizumab may provide a new standard of care for hemophilia management by providing an effective, safe, and convenient option for pediatric patients with hemophilia A," concluded lead investigator Guy Young, MD, director of the hemostasis and thrombosis program at Children's Hospital Los Angeles and the University of Southern California.

Presenting the new data here at the American Society of Hematology (ASH) 2017 Annual Meeting, Dr Young also described the effect the drug is having on the lives of these young patients.

"Before this drug, we didn't have very effective ways to prevent joint bleeding in these patients," he commented. "This drug has demonstrated a very high level of efficacy at preventing those bleeding events. It's been life-changing for the children I've treated."

It's been life-changing for the children I've treated. Dr Guy Young

Dr Young explained that patients with hemophilia A suffer from debilitating bleeding events, especially in the joints, which cause significant pain in the short term, as well as long-term joint disease. Treating the patients with frequent intravenous factor VIII concentrate leads to neutralizing antibodies in ~30% of patients.

Patients who develop the neutralizing antibodies (or inhibitors) have until now been treated with immune tolerance induction or bypassing agents. "However, for approximately 8% of these patients, this approach is not effective," Dr Young noted.

Bypassing agents are "disruptive therapies," he commented. The development of inhibitors is disruptive, and he quoted a mother of a patient: "I wish my son had plain old hemophilia."

Bypassing agents, which need to be administered intravenously two to three times a week, pose a treatment burden on patients and their families, he explained. These frequent intravenous infusions often require long-term use of central venous access devices for pediatric patients, which may be complicated by infections and thrombosis. In addition, the bypassing agents are prohibitively costly, and central line complications are associated with nonadherence to therapy.

Emicizumab may well change the treatment landscape for patients with hemophilia A, he suggested. Because it is an antibody, it is not expected to induce factor VIII inhibitors or be affected by inhibitors in patients who have them, Dr Young explained.

Emicizumab is a first-in-class bispecific monoclonal antibody, which bridges two factors in the coagulation cascade: activated factor IX and factor X, essentially replacing the missing factor VIII in hemophilia A. It is self-administered once weekly via subcutaneous injection.

"Emicizumab provides a change in the quality of life of patients and their families in dramatic and meaningful ways," he said.

Details of HAVEN 2 Results

HAVEN 2 is a single-group, multicenter, open-label, phase 3 clinical study, which enrolled pediatric patients with hemophilia A with factor VIII inhibitors. Initially, patients enrolled were between 2 and 12 years of age (or up to 17 years of age if <40 kg). "Enrolling patients between 12 and 17 years of age with weight less than 40 kg allowed us to enroll patients who were excluded in HAVEN 1," Dr Young said.

Later, patients younger than 2 years were also enrolled. All patients were previously receiving prophylactic or episodic treatment with bypassing agents.

Patients received emicizumab 3 mg/kg once weekly subcutaneously for the first 4 weeks, and then 1.5 mg/kg also once weekly for 52 weeks.

Data were reported at ASH 2017 for the second interim analysis; the final primary analysis is to be undertaken 52 weeks after the last patient is enrolled.

The updated data included 60 patients: 57 were younger than 12 years, including 2 who were <2 years of age and ~6 additional months of data vs the first interim analysis.

Most patients (57/60; 95%) had severe hemophilia, and approximately three fourths (44/60; 73.3%) received previous prophylactic treatment. Baseline characteristics reported that patients had a median of 6 bleeds in the 24 weeks before emicizumab prophylaxis.

At a median follow-up time of 9 weeks, 20 patients were observed for more than 6 months, and 2 patients aged <2 years for ~5 weeks and ~2 weeks.

Efficacy data for patients younger than 12 years (n = 57) indicated that ~95% (54/57) of patients had zero treated bleeds. Only 3 treated bleeds were reported: 1 in the joint, 1 in a muscle, and 1 in the hip. All were treated with recombinant factor VIIa (also known as bypassing agent), which is standard therapy for patients with hemophilia A and inhibitors.

Of 57 patients, no bleeds were reported in 37 patients (~65%); 56 patients showed no treated joint bleeds (98%), and all patients showed zero treated target joint bleeds.

For patients remaining on study for at least 12 weeks who were younger than 12 years (n = 23), annualized bleeding rate was 0.2% for treated bleeds, 2.9% for all bleeds, and 0.1% each for treated spontaneous bleeds and treated joint bleeds.

In a cohort of 13 patients, Dr Young showed the intrapatient annualized bleeding rate dramatically decreased with emicizumab prophyaxis; in 10 patients, the annualized bleeding rate was 0.

HAVEN 2 is set to open two additional nonrandomized cohorts to investigate every-2-week and every-4-week dosing schedules.

Serious adverse events were reported in 6 patients: catheter site infection, device-related infection, eye pain, muscle hemorrhage, mouth hemorrhage, and appendicitis.

No thromboembolic or thrombotic microangiopathy events were reported.

Safety issues attributed to concomitant use of emicizumab and bypassing agent were not seen in HAVEN 2. "Such problems have not occurred in this trial, likely in large part due to the fact that the patients on this trial rarely used bypassing agents since they had so few bleeding events," Dr Young said in an ASH news release.

Speaking at an ASH press conference, Margaret Ragni, MD, professor of medicine at the University of Pittsburgh, Pennsylvania, and ASH expert on hemophilia, said the new data are "outstanding and unusual." The report of remarkable benefits of a more easily administered therapy promises to change the standard of care for patients with hemophilia A, she noted.

Dr Ragni explained that emicizumab offers the chance to individualize therapy. "Patients with mild or moderate hemophilia A may continue to remain on their current therapy," she said.

There is also the additional advantage of dosing convenience: "Emicizumab offers the convenience of a subcutaneous therapy compared with the intravenous injections required with bypassing agents," Dr Ragni said.

New Results for Extended Dosing

At this meeting, interim results were also presented for HAVEN 4, which looked at the feasibility of an extended dosing interval with emicizumab. HAVEN 4 is a phase 3 study in adults and adolescents with hemophilia A with or without inhibitors to factor VIII. The results were reported to be consistent with those reported for HAVEN 1 and HAVEN 2.

Preliminary data from 7 patients reported that once-every-4-week dosing at 6 mg/kg demonstrated a pharmacokinetic behavior that was consistent with data with 1.5 mg/kg weekly dosing. After a median of 17 weeks, emicizumab prophylaxis provided a clinically meaningful control of bleeding. HAVEN 4 is now fully enrolled, with 48 patients.

The future may provide additional dosing schedules for emicizumab. Data from HAVEN 4 open the potential for once-monthly dosing.

At this time, emicizumab is approved at the dosing schedules used in the HAVEN 1 and 2 studies: 3 mg/kg given subcutaneously once weekly for the first 4 weeks, followed by 1.5 mg/kg once weekly.

In addition, data from the HAVEN studies are expected to support the use of emicizumab across all patients with hemophilia A, with or without factor VIII inhibitors. HAVEN 3 is evaluating emicizumab in patients with hemophilia A without inhibitors to factor VIII.

The HAVEN studies are sponsored by Roche/Genentech. Dr Young has reported receiving honoraria and/or consulting fees from Alnylam, Bayer, Bioverativ, CSL Behring, Genentech/Roche, Kedrion, Novo Nordisk, and Shire. Dr Ragni has reported receiving consulting fees, honoraria, and/or research funding from Alnylam, Bayer, Bioverativ, Biomarin, Genentech/Roche, MOGAM, NovoNordisk, Sangamo, Shire, and SPARK.

American Society of Hematology (ASH 2017) Annual Meeting: Abstract 85. Presented December 9, 2017.

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