Real-world Use Supports Effectiveness of Advate, Adynovate, and Feiba, Takeda Data Show

Takeda presented new real-world data highlighting the underdiagnosis of hemophilia A and B, supporting the effectiveness and safety of its hemophilia therapies — Advate, Adynovate, and Feiba — and discussing potential benefits of personalized therapies.

The company presented these latest data at the 13^th Annual Congress of the European Association for Haemophilia and Allied Disorders (EAHAD 2020), held Feb. 5–7 in the Netherlands.

The poster “Incidence and Prevalence of Diagnosed and Undiagnosed Hemophilia A and Hemophilia B in the United Kingdom, Germany, France, Italy, and Spain” (P050) described the findings from a literature review showing that a substantial number of mild to moderate cases of hemophilia A and B remain undiagnosed, suggesting the prevalence of these bleeding disorders “may be higher than recognized.”

In the five European countries studied (U.K., Germany, France, Italy, and Spain), the estimated percentage of undiagnosed cases ranged from 16% to 47% for hemophilia A, and from 34% to 65% for hemophilia B. Diagnosis rates varied with disease severity, its researchers said, with highest rates typically associated with more severe disease.

“Many of us are aware that hemophilia is underdiagnosed, but we don’t necessarily have access to data that show a comprehensive picture of the overall rate of undiagnosed cases in a certain region,” Dan Curran, MD, head of the Rare Diseases Therapeutic Area Unit at Takeda, said in a press release.

“Our study, which looks at the incidence and prevalence of diagnosed and undiagnosed hemophilia A and hemophilia B in EU5 countries, provides more clarity, and the findings continue to motivate our work with the bleeding disorders community to improve diagnosis,” Curran added.

In the poster “AHEAD International and German studies: 6-year interim effectiveness and safety outcomes in patients with hemophilia A receiving antihemophilic factor (recombinant) in a real-world setting,” (P115), the company presented data from two large multicenter studies — AHEAD International (NCT02078427) and AHEAD German (DRKS 00000556) — that evaluated the long-term safety and effectiveness of Advate (recombinant antihemophilic factor [rAHF]; octocog alfa) in people with moderate-to-severe hemophilia A.

The two studies, collectively known as AHEAD, are some of the largest, long-term, real-world studies ever carried out on hemophilia. AHEAD International, which opened in June 2011, is underway across 22 countries, and currently still recruiting at some locations. AHEAD German is also enrolling patients in Germany; more details are available here.

A six‐year preliminary analysis that includes 1,089 hemophilia A patients, using Advate prophylactically or on-demand to prevent or control bleeds, supported the therapy’s long-term effectiveness and tolerability regardless of disease severity in real-life clinical practice.

In the poster “Immunogenicity Profile of Rurioctocog Alfa Pegol in Previously Treated Patients with Severe Congenital Hemophilia A: Findings from 6 Clinical Trials” (P187), researchers assessed if Adynovate (recombinant antihemophilic factor, PEGylated, TAK-660) could trigger the formation of inhibitors (antibodies that render treatment ineffective) and studied their impact on treatment efficacy and safety.

Pooled data from six Adynovate trials — NCT01599819, NCT01736475, NCT01913405, NCT01945593, NCT02210091, and NCT02585960 — showed that none of the 360 patients with severe hemophilia A developed persistent inhibitors to treatment. Apart from one person, none of the remaining 359 participants tested positive for these inhibitors at any time point.

Fifty-four patients had an antibody response at some point during the trials, but 34 of them already had antibodies targeting blood clotting factor VIII (FVIII), PEG, or both, prior to treatment with Adynovate.

None of such immune responses altered Adynovate’s efficacy or were associated with severe side-effects, indicating the medicine does not increase the risk of inhibitors or harmful immune responses, the team concluded.

In the poster “Safety and Effectiveness of Activated Prothrombin Complex Concentrate (aPCC) Monotherapy in Patients with Hemophilia and Inhibitors (PwHI) Undergoing Surgery: A Systematic Review and Meta-Analysis” (P114), investigators analyzed 14 studies reporting the clinical outcomes of 158 patients with hemophilia who had surgery and were treated with Feiba (anti-inhibitor coagulant complex) to control eventual bleedings.

In this setting, Feiba was associated with a low rate of thromboembolic events (formation of clots that can clog blood vessels). No cases of thrombotic microangiopathy (clogging of small blood vessels) were reported. The therapy’s effectiveness was rated as excellent or good in over 90% of the surgeries.

“Getting a treatment to market is just the beginning,” Curran said. “Gathering evidence on an ongoing basis from day-to-day medical practice, outside of rigorous clinical studies, is critical.”

In addition to its real-world studies, Takeda presented the findings from a post-hoc analysis of a Phase 3 trial in the oral communication “Rurioctocog Alfa Pegol PK-guided prophylaxis targeting two FVIII Trough Levels in Severe Hemophilia A Patients (PROPEL Phase 3 Study): Impact of Patient FVIII Half-Life on Consumption and Efficacy Outcomes” (OR09), focused on the importance of personalized therapies.

The analysis used data from the PROPEL trial (NCT02585960) to highlight the importance of personalizing Adynovate dosing to achieve adequate levels of FVIII in each patient.

Researchers measured how long Adynovate’s active ingredient stayed in the blood of 95 men with hemophilia A, a drug property known as pharmacokinetics. Guided by that, prophylactic dosing of the medicine was tailored to each patient.

Patients whose body eliminated Adynovate faster seemed to require higher doses and more frequent infusions to achieve FVIII levels adequate for bleed protection, compared to those whose body eliminated Adynovate at a slower pace.

“As technology advances, we are able to tailor everything around us to suit our needs and that should include medical treatments,” said Wolfhard Erdlenbruch, MD, vice president of Head of Global Medical Affairs Hematology at Takeda. “We cannot assume that one regimen or one dosing strategy is going to be suitable for all.”