Milds Matter—Feasibility of Emicizumab Prophylaxis in Mild Hemophilia

1.

The treatment paradigm for hemophilia A has evolved significantly with the advent of extended half‐life (EHL) and ultra‐long EHL factor VIII (FVIII) products, along with non‐factor therapies like emicizumab, and the rebalancing agents, concizumab, marstacimab, and fitusiran. While prophylaxis has been standard of care for severe hemophilia A (FVIII activity <1%), treatment for mild hemophilia (FVIII >5%–40%) has been limited to on‐demand use for breakthrough bleeding and perioperative hemostatic management. Despite their classification as “mild,” persons with mild hemophilia (PWmH) may experience significant bleeding episodes (particularly with intense physical activity, following injury or from invasive medical procedures) and joint damage [1, 2]. With the availability of low‐burden, subcutaneous, and long‐acting prophylactic therapies, there exists a compelling argument to extend prophylaxis to PWmH to close the treatment gap and promote health equity [3, 4, 5]. As prophylactic goals for moderate and severe PWH no longer target trough factor VIII levels of 1%–2%, there is the potential for PWmH to remain at lower levels and be offered less protection without prophylaxis [6, 7, 8]. We initiated a limited‐institution study to prospectively investigate the hemostatic characteristics and efficacy of weekly prophylactic emicizumab in children and adults in PWmH, as measured by number of bleeding events and/or requirement for alternative hemostatic agent for interventions and recorded use of alternate hemostatic therapies (FVIII, DDAVP/desmopressin acetate) to treat bleeding.

After IRB approval and consent, male patients with a diagnosis of mild hemophilia A (FVIII >5%–40%), ages 5 to 45 years with any number of exposure days were considered for enrollment and study‐provided emicizumab. Those with a secondary bleeding diagnosis, current or history of inhibitor, elevated BMI >40, or history of cardiovascular disease or high risk for thrombotic microangiopathy were excluded. At the time of the interim analysis presented here, 11 patients were enrolled and completed study visits at 4, 7, 10 and 13 months. Upon enrollment, demographic and lab data were obtained. PWmH received emicizumab at 3 mg/kg once weekly for four weeks (loading doses) followed by emicizumab at 1.5 mg/kg once weekly for 13 months. Patients could then elect to continue therapy for an additional 12 months (total of 25 months on study). Laboratory data, bleeding events and adverse events were recorded at baseline and during study visits at month 4, 7, 10, and 13. To assess joint health, a six‐joint baseline musculoskeletal ultrasound (MSKUS) was performed (per HEAD‐US protocol) at enrollment and after 13 months on study.

Our study included 11 mild hemophilia A participants: all were male, primarily white (non‐Latino), with a body mass index <40 (14.9–35.3), and FVIII ranging from 6%–37%. We compared the treated annualized bleed rate (tABR) from three periods including six‐years prior to enrollment, one‐year prior to enrollment and during the 13‐month on‐emicizumab segments. Both the one‐year and six‐year prior segments were evaluated to characterize the PWH's longer‐term bleeding phenotype as well as account for their bleeding in the year immediately prior to enrollment. The median within‐subject tABR on emicizumab versus the preceding year was 0.00 [IQR 0.00–0.50], indicating that most participants remained bleed‐free or experienced few bleeds on emicizumab. In contrast, the longer six‐year baseline comparison (Post vs Pre‐all: 3.30 [IQR 0.00–5.91]) yielded a higher median ratio (Table 1). While on emicizumab, five participants experienced one or more bleeding events. Patient 2 developed a hematoma in the soft tissue of the elbow due to a fall (prior to the fourth loading dose of emicizumab) and received one dose of standard half‐life recombinant factor VIII (SHL rFVIII). Patient 3 experienced a thigh contusion resulting from a bike injury which was treated with two doses of B‐domain deleted SHL rFVIII. Patient 7 developed wrist soft tissue swelling without hemarthrosis after a fall and utilized DDAVP (desmopressin acetate). Patient 9 experienced five bleeding events due to injuries including hamstring strain during basketball, left arm trauma after a fall, right knee swelling and left knee abrasion due to a fall, a head contusion from playground equipment and a hand laceration from an injury with a metal fragment. All injuries resolved with a single infusion of ultra‐long half‐life (UHL) rFVIII infusions except for the left arm trauma which required a second infusion. Patient 10 experienced four bleeds including left index finger jam during basketball, leg burn from motorcycle exhaust, left upper quadrant intra‐abdominal hematoma sustained after repeated diving into a lake from a height, and left foot bleed. Each injury resolved with treatment with UHL rFVIII. However, due to hematoma formation, the intra‐abdominal bleed required approximately two months of therapy for complete resolution, as monitored by MSKUS.

TABLE 1.

Treated annualized bleed rate in persons with mild hemophilia A.

Participant #	Age in years	Baseline factor VIII activity (One‐stage %)	Historical tABR (6‐years prior)	Historical tABR (1‐year prior)	On‐treatment tABR	On‐treatment bleed reason
1	24	9	0	0	0
2	17	37	0.3	0	1	Activity
3	31	11	0.15	0	1	Activity
4	14	17	1.4	2	0
5	44	13	0	0	0
6	8	6	0.13	0	0
7	12	8	0	0	1	Activity
8	24	7	1.31	2	0
9	14	16	0.13	0	5	Activity
10	15	6	0.77	4	4	Activity
11	36	22	0	0	0

Abbreviation: tABR, treated annualized bleeding rate.

Study bleed data may reflect reporting bias as subjects may have been more likely to report and thus treat their bleeding episodes during study enrollment. Despite emicizumab prophylaxis, five patients experienced a bleed necessitating treatment during the 13‐months enrollment. Their experience demonstrates that PWmH may experience bleeding episodes, require factor therapy and may benefit from prophylaxis.

Changes in joint health were tracked via point‐of‐care MSKUS and scored in accordance with the HEAD‐US protocol. Patient 1 had an increase in their HEAD US score (from 0 to 1) resulting from cartilage thinning in his medial left knee due to progression past traumatic injury which had required surgical intervention prior to study enrollment. Patient 7 scored a 1 at baseline and at 13 months due to synovial proliferation in the right knee. The remaining participants (9/11) scored 0 at baseline and 13 months.

Seven patients (74%) elected to continue into the year two extension portion of the trial and remain on emicizumab. Generally, participants cited improved sense of protection from bleeding and/or the continued desire to improve knowledge of how best to treat PWmH.

As was seen in the HAVEN trials [3], injections site pain was reported by one participant. There were no serious adverse events, adverse events of special interest or development of neutralizing antidrug antibodies during the study.

Limitations of the study include a small sample size. Despite opportunities to enroll, several PWmH declined due to perceived lack of bleeding risk. Further, the 13‐month study duration may not sufficiently capture bleeding tendency/events in PWmH as bleeding most commonly results from injury or invasive procedures. Lastly, musculoskeletal changes due to prior bleeding events are more likely to become evident throughout a patient's lifetime and may not have had adequate time to be detected.

Emicizumab was safe and well tolerated in our small cohort of PWmH. While baseline bleeding rates were low in some individuals, our findings suggest that emicizumab prophylaxis may still represent a reasonable strategy for selected patients, particularly those who have an increased bleeding phenotype, participate in regular sports or physically demanding activities, or experience injury‐triggered joint morbidity. In individuals with very low baseline tABR, the benefit of prophylaxis may extend beyond reduction in bleeding frequency to include prevention of activity‐related bleeds, reduced treatment burden, and improved participation in daily activities. As novel therapies that more fully normalize hemostasis continue to emerge, the role of prophylaxis in mild hemophilia may further evolve. By focusing on individual bleeding phenotypes and patient‐centered outcomes, clinicians may better tailor treatment strategies to improve quality of life and long‐term outcomes for people with hemophilia.

Funding

This study was supported by grant funding from Genentech/Roche.

Data Availability Statement

The data that support the findings of this study are available from the corresponding author, [KAD], upon reasonable request.