Prophylactic (preventive) treatment with Adynovate safely and effectively lowers the number of bleedings, including those in target joints, in children and adults with severe hemophilia A, according to data from two Phase 3 clinical trials.
Notably, personalized Adynovate treatment targeting higher minimum blood levels of factor VIII (FVIII) — the missing or defective clotting factor in people with hemophilia A — was associated with even greater benefits, but no safety changes or issues. Also, target FVIII levels were frequently attainable with the standard every-other-day treatment regimen.
These and other findings from Takeda’s research program in hemophilia A were presented through three company-sponsored posters at the Thrombosis & Hemostasis Summit of North America (THSNA) 2020 Virtual Conference, held Oct. 27–30.
“When living with a bleeding disorder that is complex, rare and lifelong, it is critically important to strive for personalized care, to help patients find an appropriate therapy option for them,” Jonathan C. Roberts, MD, said in a press release. Roberts is the associate medical and research director at the Bleeding & Clotting Disorders Institute, in Peoria, Illinois.
“The opportunity for therapeutic individualization with factor products provides hope that bleeding disorder patients can live life with treatment plans that help to address their clinical needs,” added Roberts, who also is a professor of pediatrics at the University of Illinois College of Medicine at Peoria.
Adynovate, an injectable replacement therapy for hemophilia A, delivers a lab-made FVIII bound to a non-toxic molecule called polyethylene glycol, which allows it to stay in the blood longer than its predecessor, Advate.
In the poster, “A Phase 3b, open-label, multicenter, Continuation study of rurioctocog alfa pegol prophylaxis in previously treated patients with severe hemophilia A: clinical outcomes in patients with target joints by age group,” researchers presented Adynovate’s effects on target joint bleedings across different age groups.
The Phase 3b Continuation study (NCT01945593) evaluated the long-term safety and effectiveness of Adynovate in 216 severe hemophilia A patients (215 males) who previously had received FVIII replacement therapy.
Participants, with a median age of 20 (range 1–61 years), were given Adynovate twice weekly at doses designed to keep FVIII trough levels at 3% or more of those normally present in the blood. (Trough level refers to the lowest concentration of the clotting factor reached in the patient’s blood.)
Previous results showed that long-term Adynovate prophylaxis continued to safely reduce bleeding events over multiple years in children and adults with severe hemophilia A.
Focusing on target joints
Now, the scientists focused on the therapy’s preventive effects in target joints — defined as those with three or more bleeding episodes in six consecutive months — which were considered resolved if no bleeds occurred over a similar period.
Newly presented data showed that at study start, 50.9% of participants had at least one target joint. The presence of target joints increased from 6.3–27.3% in younger patients (younger than 12) to 40% in adolescents and 71.9% in adults.
At the end of the trial (after a mean of 2.2 years), 87.3% of these patients saw their target joints resolved and only 6.5% of all participants had one or more target joints — none of those younger than 6, 6.1% of those between 6 and 11, 10% of adolescents, and 7.4% of adults.
“In this population of pediatric and adult patients with severe hemophilia A, [Adynovate] prophylaxis was associated with target joint resolution in most patients in all age groups, confirming findings from previous [Adynovate] studies,” the researchers wrote.
In another poster, “Efficacy and Safety Results from a Phase 3, Randomized, Multicenter Study of Rurioctocog Alfa Pegol Pharmacokinetic-Guided Prophylaxis Targeting Two Factor VIII Trough Levels in Patients With Severe Hemophilia A (PROPEL Study): A Consideration for Personalized Prophylaxis,” the investigators showed results of a pharmacokinetic-guided Adynovate treatment strategy.
Pharmacokinetics refers to a therapy’s movement into, through, and out of the body.
The PROPEL study (NCT02585960) previously showed that personalized Adynovate’s treatment targeting higher trough FVIII levels was more effective than targeting the standard trough levels in preventing bleeds in people with severe hemophilia A.
In the study, 115 male patients were assigned randomly to receive either a high-target (trough levels of 8–12%; 58 patients) or a standard-target — trough levels of 1–3%; 57 patients — Adynovate regimen for one year.
New data showed that during the last six months of treatment, a significantly greater proportion of patients given the high-target regimen (67%) stopped having bleedings, compared with those receiving the standard-target treatment (40%).
Notably, while dosing was more frequent in the high-target regimen group, 60% of these patients achieved target troughs with the standard every-other-day FVIII regimen, with only 12% requiring daily dosing.
Adynovate’s safety profile was consistent with that reported in previous trials, and similar between the two dosing regimens. Adverse events (side effects) occurred in 61% of all participants and serious adverse events in 6%.
“PROPEL is the first prospective Phase 3 study with proof-of-concept that patients with severe hemophilia A can benefit from elevated FVIII troughs without change in [adverse events],” the team wrote, adding that the data “emphasize that personalized treatment for severe hemophilia A should be considered.”
They also said that patients with favorable pharmacokinetics profiles may achieve 8–12% FVIII troughs with a twice-weekly or more extended Adynovate regimen.
The poster, “Implementing GOAL-Hēm, a Goal Attainment Scaling Instrument,” focused on data from a goal attainment scaling (GAS) for hemophilia (GOAL-Hēm).
GOAL-Hēm is a hemophilia-specific, individualized outcome measure for enabling patients and caregivers to identify and track goals. It contains a goal menu categorized in three domains: hemophilia management, complications, and impact on life.
In the current study, researchers evaluated whether using GOAL-Hēm influenced time to complete goals, compared with the traditional open-ended GAS, in 42 North American hemophilia patients.
Patients (average age 23.6) had participated in a previous study testing GOAL-Hēm’s feasibility, and 27 of them had undergone traditional GAS interviews before using GOAL-Hēm.
Data showed that defining goals with GOAL-Hēm’s menu did not significantly influence time to completion, compared with traditional GAS without a menu. However, GAS data completeness was significantly higher when using GOAL-Hēm (100% vs. 40%).
The team also conducted a focus group with six participants and separate interviews with 12 patients or their caregivers to assess preferences in terms of GOAL-Hēm’s implementation.
All focus group participants recommended that GOAL-Hēm be introduced in a digital format at least one week before clinic visits. Two-thirds of the interviewed participants endorsed a patient app, and three suggested adding infusion tracking and bleed logs, which also was supported by two focus group participants.
GOAL-Hēm has been refined based on this feedback to optimize its implementation in the hemophilia population, the scientists said.
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