Emicizumab offers ‘new path forward’ for infants with severe hemophilia A
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SAN DIEGO — Emicizumab exhibited efficacy for infants with severe hemophilia A without factor VIII inhibitors, according to study results presented at ASH Annual Meeting and Exposition.
The agent also appeared well tolerated, results of the phase 3B HAVEN 7 study showed.
“I believe clinicians who see this data will have the confidence that they have a new path forward for how we manage these infants from very early in life and ensure we give them effective bleed control,” researcher Steven W. Pipe, MD, Laurence A. Boxer research professor of pediatrics and professor of pathology at University of Michigan, as well as medical director of the institution’s pediatric hemophilia and coagulation disorders program, told Healio.
Background
Hemophilia A is characterized by impaired thrombin generation due to deficiency of clotting factor VIII.
Prophylactic replacement of the factor VIII protein with factor VIII concentrates has been standard management for decades. However, this requires IV infusions that often are frequent due to the short half-life of factor VIII.
Starting prophylaxis early in life should be standard care, Pipe said. However, a high percentage of infants with severe hemophilia A do not receive prophylaxis until they turn approximately 1 year old because of challenges related to factor VIII administration. These include venous access issues and risks associated with central venous access devices, Pipe said.
Emicizumab (Hemlibra, Genentech) is a bispecific humanized monoclonal antibody that bridges activated factor IX and factor X to substitute for the function of deficient activated factor VIII.
The agent — approved in the United States for routine prophylaxis of all individuals with hemophilia A — is administered via weekly subcutaneous injections, enabling earlier initiation of prophylaxis. Its half-life approaches 30 days.
However, the studies that led to emicizumab’s approval were underrepresented for very young infants, Pipe said.
“There had been calls for a dedicated trial in the infant age group so we could really see the safety and efficacy of emicizumab in this vulnerable population,” Pipe said.
This prompted initiation of the multicenter, open-label HAVEN 7 study, which assessed the effectiveness, safety and pharmacokinetics of emicizumab for infants aged younger than 12 months with severe hemophilia A without factor VIII inhibitors.
Researchers hypothesized the agent could mitigate risks of untreated spontaneous and traumatic bleeding, intracranial hemorrhage — for which infants who are not on prophylactic therapy are at substantial risk, Pipe said — and factor VIII inhibitor development.
Methods
The analysis included 55 participants (median age at informed consent, 4 months; range, 9 days to 11 months 30 days; 45.5% aged younger than 3 months; 100% male) who received emicizumab for at least 52 weeks.
Twenty-five (45.5%) study participants received no treatment prior to enrollment and 30 (54.5%) had received minimal prior treatment, defined as up to 5 prior exposure days to factor VIII.
The subgroup of infants aged 0 to 3 months had a higher representation of previously untreated participants (18 vs. 7), whereas the subgroup of those aged 3 months to 12 months had a higher representation of previously treated participants (23 vs. 7).
Approximately two-thirds (65.5%) had at least one bleeding episode prior to their first emicizumab dose. Of the 77 total prior bleeds, 42.9% were due to a procedure or surgery, 32.5% were spontaneous and 24.7% were traumatic.
Study participants received a loading dose of subcutaneous emicizumab 3 mg/kg weekly for 4 weeks, followed by maintenance doses of 3 mg/kg every 2 weeks for 48 weeks.
Follow-up continued for 7 years, during which time participants could continue on the same regimen or switch to one of two other options — 1.5 mg/kg weekly every 4 weeks or 6 mg/kg every 4 weeks.
Annual bleeding rates for treated bleeds, all bleeds, treated spontaneous bleeds and treated joint bleeds served as key efficacy outcomes.
Safety endpoints included adverse events, thromboembolic events, thrombotic microangiopathies and immunogenicity, defined as development of anti-emicizumab antibodies or de novo factor VIII inhibitors.
Pharmacokinetics endpoints included plasma trough emicizumab concentrations.
Results
Median treatment duration was 100.3 weeks (range, 52-118).
Median follow-up was 101.9 weeks (range, 52.6-119.7), and median age at analysis was 29 months (range, 12-39).
Mean trough emicizumab concentrations increased during loading, with researchers reporting values of 62 µg/mL (95% CI; 58.3-65.6) at week 5 and steady-stage concentrations sustained at 57 µg/mL to 66 µg/mL thereafter.
Results showed emicizumab exhibited consistent efficacy with regard to model-based annualized bleeding rates across categories, including treated bleeds (0.4; 95% CI, 0.3-0.6), all bleeds (2; 95% CI, 1.5-2.7), treated spontaneous bleeds (0.0) and treated joint bleeds (0.0; 95% CI, 0.0-0.1).
Researchers classified all treated bleeds as traumatic. No study participant had more than three treated bleeds, and 30 participants (54.5%) had no treated bleeds.
No intracranial hemorrhages occurred.
“The study wasn’t powered to prove we could prevent all intracranial hemorrhages, but the results certainly give me confidence that this is the best therapeutic option to do that,” Pipe said.
Researchers identified no new safety signals.
All 55 study participants experienced at least one adverse event. Nine (16.4%) experienced at least one emicizumab-related adverse event, all of which were grade 1 injection site reactions.
No treatment-related serious adverse events occurred. All serious adverse events were attributed to required or prolonged hospitalization. No participants required dose modification/interruption or treatment withdrawal due to adverse events.
One participant (1.8%) developed an anaphylactic reaction after a food allergy. No deaths, thromboembolic events or thrombotic microangiopathies occurred.
All 55 participants had evaluable pharmacokinetic data. None developed anti-drug antibodies to emicizumab.
Twenty-eight participants (50.9%) had at least one factor VIII exposure day (median, 1; range, 0-10). After factor VIII exposure, 24 participants (43%) underwent testing for factor VIII inhibitors. Two tested positive — one occurred on day 603, and the other occurred just beyond 1 year after emicizumab initiation; both were previously untreated participants aged 0 to 3 months at enrollment.
Implications
When the FDA approved emicizumab, the National Bleeding Disorders Foundation’s Medical and Scientific Advisory Council urged clinicians to consider initiating emicizumab prophylaxis as early as possible to deal with the treatment gap for this population, Pipe said.
“There was some caution because we didn’t really have the clinical data to have confidence in what the efficacy and safety would be at these very early ages,” Pipe told Healio. “Now we have the trial data, so this call — not just for early prophylaxis, but for very early prophylaxis — can be embraced as a new standard of care for our youngest infants to give them this protection throughout the early years of life.”
Perspective
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Marium Malik, MD
Emicizumab is a recombinant humanized bispecific monoclonal antibody that binds to factor IXa and X simultaneously, bringing the molecules together and bypassing factor VIIIa cofactor activity. Since its approval in 2017, it has changed the management of prophylaxis for patients with severe hemophilia A — including those with factor FVIII inhibitors and those without. Its use has been extensively studied in adults and young children.Results of HAVEN7 showed the drug to be well tolerated with minimal adverse effects. Plasma drug levels were adequate to maintain hemostasis and comparable to studies done in adult population. A majority of patients did not have severe bleeding episodes, like intracranial hemorrhage.
The findings of this study are revolutionary for management of patients in this age group, especially in avoiding exposure to factor VIII concentrates and decreasing the likelihood of inhibitor development. Moreover, emicizumab is administered subcutaneously, which is particularly helpful for infants due to difficulty obtaining IV access. Early initiation of emicizumab prophylaxis for infants with severe hemophilia A should significantly lower bleeding episodes, which will — in turn — decrease the use of factor VIII concentrates, leading to decreased morbidity and improvement in lifestyle.
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Pipe S, et al. Abstract 505. Presented at: ASH Annual Meeting and Exposition; Dec. 9-12, 2023; San Diego.
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