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Emicizumab-kxwh prophylaxis reduces bleeds among children with hemophilia A
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ATLANTA — Emicizumab-kxwh prophylaxis prevented or considerably reduced bleeds among pediatric patients with hemophilia A with inhibitors, according to results of a phase 3 study presented at ASH Annual Meeting and Exposition.
Emicizumab-kxwh (Hemlibra, Genentech) — a bispecific humanized monoclonal antibody administered via weekly subcutaneous injection — also appeared well tolerated.
The findings suggest the agent could reduce the treatment and disease burden and may become a standard of care for this patient population, according to Guy Young, MD, director of the hemostasis and thrombosis program at Children’s Hospital Los Angeles and professor of pediatrics at Keck School of Medicine of USC, and colleagues.
“The importance of the study lies in the fact that the patients with hemophilia with inhibitors suffer far worse consequences than patients without inhibitors,” Young told HemOnc Today. “This innovative new therapy offers the promise of significantly reducing the bleeding events and allowing patients with inhibitors to lead more normal lives and similar to those for patients with hemophilia without inhibitors.
“The results of this study are truly remarkable,” Young added. “For such a large group of children with inhibitors to have almost no bleeding events of clinical significance is very meaningful, as the therapies we had been using — bypassing agents — could not accomplish this outcome.”
Emicizumab-kxwh — which bridges factor IXa and factor X to restore the function of missing factor VIIIa — is intended to prevent bleeds among individuals with hemophilia A with or without inhibitors. The FDA approved the agent in November for patients with hemophilia A who developed factor VIII inhibitors.
The FDA based the approval, in part, on results of the multicenter, open-label HAVEN 2 study, the largest study of pediatric patients with hemophilia A with inhibitors.
In HAVEN 2, an interim analysis of 20 patients aged 2 to 12 years showed subcutaneous, once-weekly emicizumab prophylaxis prevented or reduced bleeds and also led to clinically meaningful reductions in annualized bleed rate compared with previous bypassing agent treatment.
At ASH, Young presented an updated analysis that included efficacy, safety and pharmacokinetics data from 60 patients (median age, 7 years; range, 1-15) previously treated with bypassing agents.
The study population included 57 children aged younger than 12 years; two of those children were aged younger than 2 years. The three children aged 12 years or older all weighed less than 40 kg.
All study participants received emicizumab-kxwh prophylaxis for at least 1 year.
Researchers assessed the annualized bleeding rate with emicizumab-kxwh prophylaxis compared with prior bypassing agent treatment during a prospective noninterventional study. Other outcome measures included health-related quality of life, aspects of caregiver burden and safety parameters.
Median observation time was 9 weeks (range, 1.6-41.6). Twenty patients underwent observation for at least 24 weeks. Observation times for the two patients aged younger than 2 years were 5 weeks and 2 weeks.
Among patients aged younger than 12 years, 37 of 57 (64.9%) reported no bleeds.
The other 20 patients reported a combined 65 bleeds. Eight of those bleeds occurred in a joint, two occurred in a muscle, and 55 were classified as “other.” The majority of bleeds classified as “other” were traumatic (55.4%; n = 36), whereas 26 (40%) were spontaneous and three (4.6%) were due to surgery or another procedure.
Fifty-four (94.7%) of the 57 patients aged younger than 12 years had zero treated bleeds. The three treated bleeds — only one of which was spontaneous — included one in a joint, one in a muscle and one hip bleed classified as “other.” All three of those bleeds were safely treated with recombinant activated clotting factor VIIa.
The annualized bleeding rate analysis included 23 patients aged younger than 12 years who were followed for at least 12 weeks.
Young and colleagues reported an annualized bleeding rate of 0.2 (95% CI, 0.06-0.62) for treated bleeds; 2.9 (95% CI, 1.75-4.94) for all bleeds; 0.1 (95% CI, 0.01-0.47) for treated spontaneous bleeds; and 0.1 (95% CI, 0.01-0.47) for treated joint bleeds.
Researchers also performed an intra-individual comparison among the 13 patients aged 12 years or younger who participated in the prospective noninterventional study and had been on HAVEN 2 for at least 12 weeks. In this population, results revealed a 99% reduction in annualized bleeding rate with emicizumab-kxwh prophylaxis compared with prior bypassing agent treatment.
Young and colleagues also observed what they described as “considerable improvements” in health-related quality of life.
The most common adverse events among emicizumab-treated patients were injection site reactions and viral upper respiratory tract infections (16.7% each).
Six patients experienced a combined seven serious adverse events. These included two cases of muscle hemorrhage, and one case each of catheter site infection, eye pain, device-related infection, appendicitis and mouth hemorrhage. None of the serious events were classified as related to emicizumab.
Researchers reported no thromboembolic or thrombotic microangiopathy events.
No patients tested positive for antidrug antibodies.
Pharmacokinetic profiles appeared consistent across age groups and body weight, and they remained consistent with those observed among adolescents and adults with hemophilia A.
“Future directions for this medication in children will need to focus on two groups: children [aged younger than] 12 years old without inhibitors and, perhaps more importantly, very young children — [younger than] 1 year of age — who may benefit from starting prophylaxis at a younger age than we are currently able to do given the fact that emicizumab is given subcutaneously, [whereas factor] is given intravenously,” Young told HemOnc Today. “This could pave the way to preventing the most devastating complication of hemophilia, which is bleeding in the brain — an uncommon but not rare event that tends to occur in the first year of life.” – by Mark Leiser
For more information:
Young G, et al. Abstract 85. Presented at: ASH Annual Meeting and Exposition; Dec. 9-12, 2017; Atlanta.
Disclosures: Young reports honoraria with CSL Behring and a consultant role with Novo Nordisk. Please see the abstract for all other authors’ relevant financial disclosures.
Perspective
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Anne Neff, MD
People are very excited about the results for emicizumab. It has been described by the clinicians who take care of some of the people on this trial as a game changer in hemophilia.
A patient I treated was put on the trial somewhere else and his follow-up has been tremendous. His bleeding has stopped.
Patients with hemophilia who have inhibitors, or an immune response to factor VIII, have very significant bleeding problems that are often not controlled by available treatments. This new molecule is completely different than what we have used in the past. It is a substitute for factor VIII instead of trying to enhance the function or replace the function of it.
As with all therapies, emicizumab has to get past the insurance companies. I’m sure it will be priced very high because it is much more convenient than factor VIII.
However, it’s important to emphasize that no hemophilia treatment is perfect, and emicizumab does have some specific potential side effects or difficulties. We continue to learn about those, and it is important that follow up continues so we make sure patients are treated as safely as possible.
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