The study, “Bleeding and safety outcomes in persons with haemophilia A without inhibitors: Results from a prospective non‐interventional study in a real‐world setting,” appeared in the journal Haemophilia.
People with hemophilia A may experience bleeds even with preventive treatment — known as prophylaxis — with engineered factor VIII (FVIII), the clotting protein missing or defective in these patients. In addition, the substantial burden of regular intravenous (into-the-vein) infusions may result in some patients being unable to receive the most appropriate care.
However, researchers have not assessed bleeding, current treatment regimens, and safety in hemophilia A patients without FVIII inhibitors.
To address this, a research team analyzed real-world data of patients without inhibitors as part of a global Roche-sponsored study in 10 countries (NCT02476942), with patients treated in accordance to local routine clinical practice. Eligible participants could then enter a Phase 3 trial (NCT02847637) of Roche’s Hemlibra (emicizumab), named HAVEN 3.
All 94 patients (median age 34 years, 56.4% white) had received FVIII treatment for at least 150 days before enrollment. Those on episodic treatment — 45 patients; the remaining 49 were on prophylaxis — had to have five or more bleeds in the past six months to be eligible. The participants were monitored for a median of 29.8 weeks. Of the patients, 90 (95.7%) completed the study and 73 (77.7%) entered HAVEN 3.
The study’s primary goal was the number of treated bleeds over time. Secondary objectives included treatment type and purpose — to treat bleeds, usual prophylaxis, or prevention before activity, as well as adverse events.
Patients and caregivers were asked to complete the Bleed and Medication Questionnaire (BMQ) every day. This questionnaire included questions on bleed type (joint, muscle, or other) location (such as elbow, ankle, and knee), and cause, which could be trauma, surgery, or, if neither, spontaneous.
The number of treated bleeds was 872 of 1,066 (81.8%) in the group on episodic treatment and 151 of 189 (79.9%) in patients on prophylaxis. Bleeds were either spontaneous or due to trauma in both groups. Among treated bleeds, 71.5% occurred in the joints, especially in the elbows, ankles, and knees.
Patients on episodic treatment revealed a significantly higher annualized bleeding rate (ABR) — the number of bleeds per year — compared with people on a prophylactic regimen for both treated (36.1 vs. 5) and all bleeds (43.1 vs. 6.2).
All patients on episodic treatment had an ABR higher than 10, compared with only 22.4% in the group on prophylaxis.
The most common treatment was standard half‐life FVIII, received by 93.3% of participants in the episodic group and by 83.7% in patients on prophylaxis. Half-life refers to the time the body takes to halve the amount of a compound.
Patients adhered to the prescribed frequency of prophylactic FVIII administration for a median 86% of weeks. Two-thirds adhered to 80% or more of the prescribed doses, while 53.3% adhered to both treatment frequency for more than 80% of weeks and at least 80% of the prescribed doses.
The investigators cautioned that this high treatment adherence may have been due to the patients’ awareness that they were being monitored and to a requirement for a specific level of FVIII exposure for eligibility in HAVEN 3. So this may not reflect typical real-world results.
Most patients in the prophylaxis group (38) were prescribed standard half‐life FVIII with a median of 2.9 doses per week, while seven were prescribed extended half‐life FVIII and used a median of 2.1 weekly doses.
Fifty-one adverse events occurred in 33 patients, the most common being viral upper respiratory tract infections in 6.4% of participants. Serious side effects (five cases) only occurred in participants on prophylaxis, including a 57-year-old man with hemarthrosis — bleeding into joint spaces — and a severe gastrointestinal polyp followed by a fatal myocardial hemorrhage.
“In conclusion, results from this prospective real‐world study confirm that regular FVIII prophylaxis controls/prevents bleeding in [patients with hemophilia A] without inhibitors,” the scientists wrote, adding, however, that bleeding episodes still observed despite prophylaxis “reveals an unmet need for more effective therapies that are easier to adhere to.”
Of note, four of the study’s authors are employees of Roche. Three others have been paid consultants and received honoraria or grants from the company. The other two participated in advisory boards and/or have been members of speaker bureaus for Roche, while another two participated on advisory boards, were consultants, or received honoraria from Roche-owned Genentech.