Untreated Hemophilia A Bleeds Common, Skewing ABR: Analysis

Knowing more may enable full scope of disease burden, better therapy evaluation

Steve Bryson, PhD avatar

by Steve Bryson, PhD |

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A significant proportion of bleeds in people with hemophilia A are left untreated, according to an analysis of data from an observational study.

Because only treated bleeds are typically reported in clinical trials, these findings suggested the full disease burden is not adequately captured in many studies.

As such, researchers said there is a need to understand why bleeds remain untreated and these events should be recorded in clinical trials to provide a more comprehensive assessment of therapies.

The analysis was detailed in the study, “Untreated bleeds in people with hemophilia A in a noninterventional study and intrapatient comparison after initiating emicizumab in HAVEN 1–3,” published in Research and Practice in Thrombosis and Haemostasis.

Hemophilia A is marked by the lack of a blood clotting protein called factor VIII (FVIII). Its severity depends on the amount of FVIII the body produces. Spontaneous bleeds may occur in the joints in more severe cases, leading to joint damage. In milder cases, bleeding may occur after an injury or surgery.

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Transition to Hemlibra Safe, Effective in Children With Hemophilia A

FVIII replacement therapy is the standard of care in hemophilia A, providing an external source of FVIII to compensate for its deficiency. However, long-term replacement therapy can lead to developing inhibitors, or neutralizing antibodies that target the delivered FVIII, reducing its effectiveness.

An annualized bleeding rate (ABR) is often used as the primary outcome measure in hemophilia clinical trials. In these studies, treated bleeds are reported, but those that remain untreated usually aren’t. As a result, recorded ABRs may be underestimated since treated bleeds only account for a portion of all bleeds.

Characterizing both treated and untreated bleeds in patients on standard therapies needs to be established to compare study outcomes with nonfactor therapies such as Hemlibra (emicizumab), an approved treatment that mimics the action of FVIII, researchers noted.

An international group of researchers analyzed data from a global observational study (NCT02476942) that enrolled hemophilia A patients on standard therapy with or without inhibitors. Participants were required to record bleeds regardless of treatment.

Assessing untreated bleeds

The study included 103 adults and adolescents, ages 12 and older, with FVIII inhibitors (group A), 24 children under age 12 with inhibitors (group B), and 94 adults and adolescents without inhibitors (group C). All were male, except one adult/adolescent female with inhibitors.

Over five to seven months, untreated bleeds were assessed for site, frequency, and cause.

Untreated bleeds were reported by 74 (71.8%) patients in group A, 13 (54.2%) in group B, and 45 (47.9%) in group C. The proportion of untreated bleeds was similar between patients with inhibitors in groups A and B (39.8% vs. 40.1%), but lower in group C (26.2%).

A calculated ABR for untreated bleeds was similar for those with inhibitors in groups A and B (13.6 vs. 15.0), but notably lower in those without inhibitors in group C (7.0). This difference was mainly driven by a low ABR (1.5) in patients from group C who received prophylactic (preventive) therapy, with the ABR for those receiving on-demand treatment being higher at 12.9.

For both adult/adolescent groups (A and C), joints were the most common site of treated and untreated bleeds (54.0–70.8%) and included the knee, elbow, and ankle. In comparison, only 7.1% of untreated bleeds in children occurred in the joints, primarily the knee.

The proportion of treated muscle bleeds was similar across the three groups, while the proportion of untreated bleeds varied. In adults/adolescents with inhibitors, 13.5% reported untreated muscle bleeds, while 32.6% of adults/adolescents without inhibitors reported them. Only 7.7% of children reported this type of bleed.

Spontaneous bleeds accounted for more untreated bleeds in adults/adolescents with inhibitors than in those without inhibitors (63.0% vs. 35.8%). Untreated bleeds from surgery were lower in adults/adolescents with inhibitors than without inhibitors (0.6%–0.9% vs. 15.2%).

Causes of bleeding in those receiving on-demand therapy were generally comparable with those for the overall population, and included trauma, surgery, or spontaneous. A higher proportion of traumatic untreated bleeds in children occurred compared with all children (72.1% vs. 53.2%). More untreated bleeds were spontaneous among patients receiving prophylaxis versus on-demand treatment.

Evaluating Hemlibra

Some participants receiving standard prophylaxis in this study had entered one of three Phase 3 HAVEN trials evaluating Hemlibra. Among them, 24 adults/adolescents with inhibitors entered HAVEN 1 (NCT02622321), 14 children with inhibitors joined HAVEN 2 (NCT02795767), and 48 adults/adolescents without inhibitors enrolled in HAVEN 3 (NCT02847637).

Compared with initial standard treatment, the ABR for untreated bleeds after Hemlibra dropped from 8.5 to 2.3 in adults/adolescents with inhibitors in HAVEN 1, and from 14.8 to 4.0 in children with inhibitors in HAVEN 2. No ABR change was seen in HAVEN 3 for untreated bleeds in adults/adolescents without inhibitors (5.9 vs. 5.7).

More untreated bleeds were seen in each HAVEN study than in the observational study, but the proportion of both treated and untreated spontaneous bleeds decreased after starting Hemlibra.

Although the joints were the most treated bleed sites across all three groups, before or after HAVEN, untreated bleed locations varied. More adults/adolescents with inhibitors had untreated joint bleeds in both studies, while for adults/adolescents without inhibitors, Hemlibra led to a lower proportion of untreated joint bleeds. Untreated joint bleeds were less frequent in children than in adults.

“A significant proportion of subjectively perceived bleeds in people with hemophilia A remain untreated, suggesting that the full burden of the disease is not adequately captured in many clinical studies,” the researchers wrote. “An understanding of why some bleeding events remain untreated is needed, and capturing these events in clinical trials would provide a more comprehensive evaluation of therapies.”

The study was sponsored by Chugai Pharmaceuticals, Hemlibra’s original developer, and its parent company Roche.