Maintaining high concentrations of Adynovate in the blood of hemophilia A patients decreases the number of bleedings and enables more patients to stop having bleeds, according to the first results of a Phase 3b/4 study by Takeda.
The findings were announced at the 12th Annual Congress of the European Association for Haemophilia and Allied Disorders (EAHAD), which took place Feb. 6 to 9 in Prague, Czech Republic.
As a safe prophylatic treatment, Adynovate dosing that reaches 8 to 12 percent of factor VIII (FVIII) normal blood concentrations may help more patients reach zero bleeds than a lower dose would, the study suggests. Adynovate is sold as Adynovi (PEGylated recombinant factor VIII: BAX 855) in Europe.
Personalized treatment would involve monitoring Adynovate’s pharmacokinetic profile: its absorption, distribution, metabolism, and elimination inside each patient’s body.
The PROPEL study (NCT02585960) was a Phase 3b/4 trial comparing the safety and efficacy of Adynovate as a prophylaxis treatment on hemophilia A patients. The study was based on preliminary data indicating that higher FVIII trough levels may protect against bleeds and help more patients reach zero bleeds.
Trough level refers to the lowest concentration of the clotting factor reached in the patient’s blood. A low FVIII concentration corresponded to 1 to 3 percent of FVIII normal levels and a high level corresponded to 8 to 12 percent of FVIII normal levels.
Adynovate dosing was adjusted for each participant based on their individual pharmacokinetic profiles. After initial assessments, participants were randomized to enter one of two dosing regimens: 12-month programs to reach either a low or a high FVIII trough level.
The 115 male subjects, ranging from 12 to 65 years old, had either transitioned from a prior Adynovate study or were newly included, and had more than 150 days’ exposure to plasma-derived or recombinant FVIII.
The study’s objective was to measure the proportion of patients who stopped having bleeds during the study’s second half (last six months). It also assessed total annualized bleeding rate (ABR) — meaning the number of bleeding events per proportion of days on treatment in one year — spontaneous ABR, joint ABR, and side effects.
From the initial group of 115 hemophiliacs, 106 (56 in low-dose regimen, 50 in high-dose regimen) completed the study.
Over the study’s last six months, bleeding had stopped in more patients receiving the high dose (66%) than in the group taking the low dose (39%).
More patients (84%) undergoing the high dose of Adynovate reached zero spontaneous bleeds, compared with those taking the low dose (61%); and 90% of the high-dose group experienced zero joint bleeds versus 68% of the low-dose participants.
On average, total ABRs in the last six months of the study were 1.6 for those on the high-dose regimen, and 3.6 for those receiving the low dose.
“The zero all bleed rates and zero all spontaneous joint bleeds in this study have not been reported previously with people living with hemophilia A,” Wolfhard Erdlenbruch, MD, Takeda’s vice-president, and head of global medical affairs said in a press release. Takeda, the current owner of Adynovate marketing rights, recently acquired Shire, the company producing the medicine.
The safety profile was seen to be comparable and consistent with prior Adynovate trials, for both dosing regimens.
Side effects occurred in 63% of the participants, and serious side effects happened in 9%.
One subject in the high dosing group temporarily developed FVIII inhibitors, which resolved by the end of the study.
“The findings suggest the need to measure actual FVIII levels and show a clear trend that if we’re able to keep FVIII levels in a higher range, there may be better patient outcomes,” said Robert Klamroth, MD, head of department and director of the Comprehensive Care Haemophilia Treatment Center at the Vivantes Klinikum in Berlin, Germany.
“The study reiterates the importance of personalized prophylaxis for those living with hemophilia,” he said.