Prophylaxis with emicizumab shows promise in young children with severe haemophilia A without FVIII inhibitors

At ASH 2023, Steven Pipe discussed the primary analysis results from the HAVEN 7 study. This phase IIIb study investigated the efficacy, safety and pharmacokinetics of emicizumab in children ≤12 months of age with severe haemophilia A without inhibitors against FVIII. Prophylaxis with emicizumab proved to be effective in this young patient population, with pharmacokinetic profiles that were similar to previous studies in adult populations.

Haemophilia A is an inherited bleeding disorder characterised by impaired thrombin generation due to deficient clotting factor (F) VIII. Although starting prophylaxis early in life should be the standard of care, many infants with severe haemophilia A do not receive prophylaxis until ≥1 year of age, owing to the challenges of FVIII administration. Emicizumab, a humanised bispecific monoclonal antibody, bridges activated FIV and FX to substitute the function of the deficient activated FVIII and can be administered subcutaneously. The HAVEN 7 study was developed in collaboration with the haemophilia A community to generate additional evidence for the prophylactic treatment of young infants living with the condition.

Study design

HAVEN 7 is a multicentre open-label phase IIIb study that enrolled children ≤12 months with severe haemophilia A without FVIII inhibitors.  Patients received subcutaneous emicizumab 3 mg/kg weekly for 4 weeks, then every 2 weeks for 52 weeks. For the 7-year long-term follow-up, participants could continue on this dosing regimen or switch to either 1.5 mg/kg weekly or 6 mg/kg every 4 weeks. Efficacy outcome measures were the number of treated bleeds, all bleeds, treated spontaneous bleeds and treated joint bleeds. Annualized bleed rates (ABRs) were calculated using a negative-binomial regression model. Safety outcome measures were adverse events (AEs), thromboembolic events, thrombotic microangiopathies, and immunogenicity (i.e. anti-emicizumab antibodies [ADAs] incidence and de novo FVIII inhibitors development). The pharmacokinetics of emicizumab were assessed using plasma trough levels.

Results

At the time of the primary analysis (May 22, 2023), 55 participants had been treated with emicizumab for at least 52 weeks, with a median treatment duration of 100.3 weeks. Median age of the patients at enrolment was 4.0 months (range 9 days – 11 months 30 days) and all patients were male. Prior to the study, 30 children (54.5%) were minimally treated (≤5 exposure days), and 25 (45.5%) were previously untreated participants (PUP). No treated spontaneous bleeds were observed in the study and all treated bleeds were categorised as traumatic. No participant had more than three treated bleeds and thirty patients (54.5%) had zero treated bleeds. Emicizumab dose was up-titrated to 3 mg/kg QW in one patient, per investigator request on decreasing emicizumab levels.

All participants experienced at least one adverse event (AE). Nine patients (16.4%) had at least one treatment-related AE; all of which were grade 1 injection site reactions. No AE led to withdrawal, dose modification or discontinuation. In total, 29.1% of patients experienced a serious AE that required hospital admission. An anaphylactic reaction occurred in one participant (1.8%) but was deemed unrelated to emicizumab. No deaths, thromboembolic events, thrombotic microangiopathies or intracranial haemorrhage were reported. None of the participants tested positive for ADAs to emicizumab. Following FVIII exposure, 24 patients (43.6%) were tested for FVIII inhibitors, with two (3.6%) testing positive. Both were PUPs aged 0-3 months at enrolment.

Following loading doses, the mean trough level was 62.0 µg/ml (95%CI: 58.3-65.6) at week 5, after which a steady state was reached with trough levels of 57-66 µg/ml. These steady-state trough concentrations were higher than those in older people with haemophilia A on the same dosing regimen in the HAVEN 1-4 studies.

Conclusion

The primary analysis of the HAVEN 7 study shows that prophylaxis with emicizumab is effective in children ≤12 months with severe haemophilia without FVIII inhibitors. Treatment was well tolerated and no new safety signals were observed. The pharmacokinetics of emicizumab in children are similar to those in adults.

Reference

Pipe S, et al. Emicizumab prophylaxis in infants with severe hemophilia A without factor VIII inhibitors: results from the primary analysis of the HAVEN 7 study. Presented at ASH 2023; Abstract 505.