Long-term Adynovate Therapy Reduces Bleeding in Severe Hemophilia A

Long-term prophylaxis, or preventive treatment with Adynovate continues to safely reduce bleeding events over multiple years in children and adults with severe hemophilia A without causing neutralizing antibodies, a Phase 3b trial found.

The study, “Long‐term safety and efficacy results from the phase 3b, open‐label, multicentre Continuation study of rurioctocog alfa pegol for prophylaxis in previously treated patients with severe haemophilia A,” was published in the journal Haemophilia.

Hemophilia A is caused by a missing or defective blood clotting protein called factor VIII (FVIII). People with the disorder often require replacement therapy, in which the missing FVIII is supplied.

Both its predecessor, Advate, and Adynovate — antihemophilic factor (recombinant) — consist of supplementary FVIII, created in a laboratory setting using recombinant technology.

In Adynovate, a non-toxic molecule called polyethylene glycol (PEG) is attached to the synthetic FVIII, which allows it to stay in the blood roughly 1.5 times longer than Advate.

To investigate its therapy, developer Baxalta (now part of Takeda) had launched six clinical trials: NCT01599819, NCT01736475, NCT01913405, NCT01945593, NCT02210091, and NCT02585960. Each was designed to assess a different facet of the treatment’s safety and efficacy.

From those studies, a total of 206 patients with severe hemophilia A were enrolled in a Baxalta-funded continuation Phase 3b trial (NCT01945593) to evaluate the long-term safety and efficacy of Adynovate. The trial was conducted at 86 sites in 23 countries between October 2013 and March 2018. Two of the study authors are employees of Baxalta and Takeda stock owners.

An additional 10 patients participated. All had received factor VIII replacement therapy, given for at least 50 days in children younger than 6, or at least 150 days in older patients.

In the continuation study, the participants received Adynovate twice weekly, via intravenous injections (directly into the bloodstream). They were given either a fixed dose of nearly 45 international units (IU)/kg in patients ages 12 or older, nearly 50 IU/kg in children under 12, or a tailored dose of up to approximately 80 IU/kg. The doses were designed to keep FVIII minimal levels at 3% or more and peak levels at a maximum of 200%.

Those ages 12 or older in the fixed dose group had the option of reducing treatment frequency to once every five days if they had no significant bleeding episodes for six months. These patients could further reduce their treatments to weekly dosing if a similar benefit was seen for another six months.

In total, the participants were observed for a mean period of 2.2 years. Their mean age at the study’s start was 22.8 years.

In up to six months before enrollment, the annual bleeding rate — or the number of spontaneous bleeding events per year — was 1.6 in the 191 patients who had received prophylaxis treatment with Adynovate. Conversely, participants who had received on-demand treatment had a bleed rate of 28.1.

Throughout the study, bleed rate decreased to 1.2 in patients receiving the fixed dose of Adynovate, and to 0.96 in those on the tailored dose.

The data also showed that the fixed dose group had a mean of 1.23 joint bleeds per year, while the tailored dose group had 1.4 joint bleeds annually.

Most patients (83.3%) had at least one bleeding episode during the course of study, the majority  of which (89.3%) were treated with one or two infusions. Hemostatic efficacy — the prevention or stop of bleeding — was rated by patents or caregivers as good or excellent in 88.5% of all bleeds.

None of the patients developed confirmed FVIII inhibitors, which are neutralizing antibodies that may render Adynovate ineffective.

Looking at the safety profile, the researchers found that, out of a total of 838 adverse events, only 20 events in 11 patients were deemed associated with Adynovate. All treatment-related side effects were mild or moderate in severity. Of 52 severe adverse events, none were attributed to Adynovate, including one death due to intracerebral bleeding from hemophilia.

“These results highlight the long‐term safety and efficacy of rurioctocog alfa pegol [Adynovate] prophylaxis in previously treated children and adults with severe haemophilia A, with a safety profile similar to previous studies and continuing ABR [annual bleeding rate] reduction,” the researchers wrote.

Finally, the scientists assessed patient-reported outcomes and found a significant improvement in Haemo‐SYM questionnaire scores, reflecting eased bleed and pain severity.

Using the SF-36 test — a set of generic, coherent, and easily administered quality-of-life measures — significant improvements were observed in 62 of 103 patients on the physical component and in 40 of 103 participants on the mental component. In addition, the PedsQL test, which measures quality of life in pediatric patients, showed clinically meaningful improvement in 24 of 39 children. However, the mean improvement was not statistically significant.