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SAN DIEGO -- Administering emicizumab (Hemlibra) to previously untreated or minimally treated infants with severe hemophilia A without factor VIII inhibitors is effective and safe, according to results from research presented here.

The phase III HAVEN-7 study showed that at a median follow-up of 101.9 weeks, the annualized treated bleeding rate was 0.4 (95% CI 0.30-0.63) among 55 study participants, with 30 children (54.5%) having no treated bleeds, reported Steven Pipe, MD, of the University of Michigan in Ann Arbor.

The annualized bleeding rate for all bleeds was 2.0 (95% CI 1.49–2.66), with no treated spontaneous bleeds.

"This was over a median follow up of over 100 weeks, and the median age was 29 months -- so these are totally mobilized toddlers through this clinical cut-off date." Pipe said during a press briefing at the annual meeting of the American Society of Hematology, "Emicizumab prophylaxis really demonstrated consistent efficacy across all the bleeding endpoints."

For decades the approach to managing hemophilia has been the use of prophylactic factor VIII protein with factor VIII concentrates. Pipe pointed out this is a challenging process because it requires intravenous infusions frequently because of the short half-life of factor VIII.

Emicizumab is a humanized bispecific monoclonal antibody that bridges factor IX and Factor X to substitute for the function of deficient activated factor VIII, and is approved for the routine prophylaxis of persons with hemophilia A.

However, Pipe observed that infants were underrepresented in studies evaluating emicizumab and so was initiated in order to provide more evidence for the prophylactic treatment of this population.

Prophylaxis should be the standard of care for infants with hemophilia A, Pipe suggested, but many don't start receiving prophylaxis until after their first year of life, mostly due to challenges and complications associated with factor VIII administration, such as venous access issues -- including situations in which clinicians have had to rely on central venous access devices.

Emicizumab, on the other hand, can be administered subcutaneously from the time of hemophilia A diagnosis, Pipe explained, "This allows us to meet this treatment gap in the first year of life by enabling very early initiation of prophylaxis, and really may mitigate the risk of untreated or spontaneous traumatic bleeding, which can accrue damage, particularly into joints."

"Importantly, it could mitigate the risk of intracranial hemorrhages," Pipe added. "There is a substantial risk of intracranial hemorrhage throughout the first year of life for infants who are not yet on prophylactic therapy."

He also noted that the study offered the opportunity to look at alterations of the natural history of inhibitor development to factor VIII-containing products, "because we would expect infants to have reduced exposure."

The 55 participants in the study were all male. Median age at enrollment was 4.0 months, with 45.5% under the age of 3 months, and 54.5% between the age of 3 months and 1 year. All received emicizumab for at least 52 weeks, with a median treatment duration of 100.3 weeks.

Prior to the study, 30 (54.5%) infants were minimally treated (≤5 exposure days), and 25 (45.5%) were previously untreated. Participants received subcutaneous emicizumab 3 mg/kg weekly for 4 weeks, then every 2 weeks for 52 weeks. For the study's 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.

Overall, 207 bleeds (treated or untreated) were reported in 46 participants (83.6%), while 42 treated bleeds, all traumatic, were reported in 25 participants (45.5%). None of the children had >3 treated bleeds, 37 (67.3%) had 0-3 bleeds, and 9 (16.4%) had no bleeds. Two participants had >10 bleeds, all untreated, and none in joint/muscle.

Pipe said no new safety signals were identified, no participants developed anti-drug antibodies directed against emicizumab, and the factor VIII exposure rates were low.

Treatment-related adverse events occurred in 9 patients and all were grade 1 injection site reactions, typically redness or irritation. No adverse events led to withdrawals, dose modifications, or interruptions, "Importantly no intracranial hemorrhages were reported in this cohort," Pipe said.

Pipe reported that all 55 participants were evaluable for immunogenicity in order to show they had no anti-drug antibodies to emicizumab, and that in about half (28) there was at least one factor VIII exposure. Following factor VIII exposure, 24 participants were evaluated for a factor VIII inhibitor; only two tested positive.

"So this is quite a low rate, but it is related to the really infrequent exposures to factor VIII," Pipe said. "What's notable about emicizumab is that its efficacy is not impacted by the appearance of a factor VIII inhibitor, so that patients can continue on prophylaxis with emicizumab, and the two children who tested positive for factor VIII inhibitors have continued on with emicizumab."

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