Bleeding Disorders
Fusion Protein Therapies for Hemophilia A and B
Patients with hemophilia A and B may benefit from the
less-frequent dosing regimens of two recently FDA-approved
fusion protein therapies: recombinant coagulation factor VIII
(FVIII) Fc fusion protein for hemophilia A and recombinant coagulation factor IX (FIX) Fc fusion protein for hemophilia B.
“This is truly an exciting time in clot factor
management,” said Margaret Ragni, MD, MPH,
who discussed the safety, efficacy, and clinical implications of these new therapies during a Special
Education Session on drugs newly approved by
the U.S. Food and Drug Administration, at the
56th ASH Annual Meeting. “They represent what
may be a paradigm shift in treatment because
Margaret Ragni, MD,
there is the potential for fewer infusions with
MPH
longer protection from bleeds, improved quality
of life, and possibly reduced immunogenicity.”
However, there are lingering questions about the appropriate use
of these recently approved agents, Dr. Ragni noted, such as: “Will it be
necessary to perform pK assessments on each patient? Will children
require more frequent dosing than adults? Will each protein require
different laboratory monitoring?”
Three presentations at the annual meeting provided more information about optimizing the use of these newer, longer-lasting clotting
factor proteins in hemophilic patients.
dose per infusion, and the percentage of bleeding episodes resolved
with one infusion were reported. Both agents were well-tolerated, with
no observed vascular thrombotic events.
Using a pharmacokinetic modeling approach, investigators predicted factor VIII and IX activity levels in scenarios in which bleeding
episodes were treated in close proximity to a scheduled prophylactic
dose. In both the A-LONG and B-LONG trials, predicted factor activity
levels were within the normal range for the majority of patients, even
among patients on prophylactic regimens with short intervals (TABLE).
rFVIIIFc in Children with Severe Hemophilia A
As Dr. Ragni mentioned in her discussion of rFVIIIFc, prophylactic
treatment of hemophilia A in pediatric patients is difficult. “In children,
prophylaxis requires placement of ports that could be associated with
infection and sepsis,” she noted, “so it is not standardly used in this
population.”
In the global, multicenter, phase 3 Kids-ALONG trial, investigators
evaluated the safety and efficacy of rFVIIIFc in previously treated young
patients with severe hemophilia A.
Guy Young, MD, presented results from 71 patients (<6 years,
n=36; 6 to <12 years, n=35) in the study who received twice-weekly
prophylactic infusions of rFVIIIFc (25 IU/kg on day 1, 50 IU/kg on day
4). Dose and frequency were adjusted as needed.
As with adult and adolescent patients, the half-lives of rFVIIIFc in
children was prolonged compared with FVIII:
Predicting Factor Activity in A-LONG and B-LONG
Currently, there are few data on clotting factor activity levels and
efficacy in hemophilic patients on routine prophylaxis who received
rcFVIIIFc and rcFIXFc for treatment of bleeding episodes. At the annual meeting, two analyses looked at the effect of these drugs in patients
receiving routine prophylaxis:
• rFVIIIFc in previously treated patients with severe hemophilia A in
the A-LONG trial
• rFIXFc in previously treated patients with hemophilia B in the
B-LONG trial
In A-LONG, patients were treated with either 50 IU/kg of rFVIIIFc
every 4 days or 50 IU/kg every 3 days (Arm 1) or weekly prophylaxis
(Arm 2); in B-LONG, patients were treated with weekly prophylaxis
(Arm 1) of rFIXFc or individualized interval prophylaxis (Arm 2).
Number of bleeding episodes, annualized bleeding rates, median
TABLE
Predicted median Cmax
• 12.67 hours (95% CI 11.23-14.11) in patients <6 years
• 14.88 hours (95% CI 11.98–17.77) in patients 6 to <12 years
Forty-six of 62 subjects (74%) who were on a prior prophylactic regimen
were also able to reduce their dosing frequency and the amount of
rFVIIIFc they received – the median average weekly prophylactic dose
administered was 88.1 IU/kg. rFVIIIFc prophylaxis was well-tolerated
and no subjects developed inhibitors.
Overall median on-study ABR was 1.96–1.50 in the <6 years cohort,
and 2.50 in the 6 to <12 years cohort. As in the adult populations, most
bleeding episodes (81.4%) were controlled with one infusion.
“Prophylaxis requires frequent infusions of FVIII, and children in
particular require more frequent infusions,” Dr. Young said, mainly due
to their shorter FVIII circulating half-lives. “Long-acting FVIII products
may allow for prophylaxis with less frequent infusions.” ●
Predicted median Cmax values after
subsequent prophylactic dose
A-LONG Trial
Every 4 days
54.8 IU/dL (95% PI 34.4-91.9)
116 IU/dL (95% PI 74.1-186)
Every 3 days
62.6 IU/dL (95% PI 37.3-112)
120 IU/dL (95% PI 74.8-196)
24 hours before next
prophylaxis dose
52.4 (95% PI 30.8-93.4)
66.8 (95% PI 41.2-114)
24 hours after previous prophylaxis dose
66.3 (95% PI 40.9-113]
54.3 (95% PI 32.1-96.6)
B-LONG Trial
2
ASH Clinical News
References
• Powell JS, Ozelo M, Ragni MV, et al.