EAHAD 2024: Fresh results of paradigm5 and 6 studies confirm safety and efficacy of N9-GP
Nonacog beta pegol (N9-GP) is a recombinant factor IX with an extended half-life. Its properties allow for the maintenance of a satisfactorily high level of FIX with intravenous application once a week. At the 17th Annual Congress of the European Association for Haemophilia and Allied Disorders (EAHAD), held in early February 2024 in Frankfurt, new findings on this treatment were presented during a satellite symposium by Novo Nordisk.
Improving treatment results, but persistent gaps in patients' quality of life
The first presentation was delivered by Dr. Sonata Šaulytė Trakymienė from Vilnius University. She began by summarizing the progress in treating hemophilia patients, mentioning the satisfactorily increasing number of patients on prophylaxis and the consequent reduction in annual bleeding rates (ABR). Despite this positive trend, the CHESS II study (Cost of Haemophilia in Europe: a Socioeconomic Survey II) found that 82% of severe hemophiliacs suffer from chronic pain and 71% have an ABR ≥ 2. According to the World Federation of Hemophilia (WFH) guidelines, a trough level of FIX of 1–3% is insufficient and does not allow for adequate prevention of occasional clinical or subclinical bleeding.
For most hemophilia B patients, the condition adversely affects how they spend their free time. They report issues with the availability and storage of medications during vacations and when engaging in recreational and sports activities. Poor adherence to treatment may be due to the inconvenience of intravenous factor therapy. Despite the good results of current therapy, pediatric hemophilia patients are at a higher risk of emotional disorders compared to peers with other chronic illnesses. A rather surprising finding emerges from the B-HEROS study, where patients with moderate hemophilia B reported a worse quality of life due to health issues compared to patients with mild or severe forms of the disease on prophylactic treatment.
The latest findings from the paradigm5 and 6 studies on the efficacy of N9-GP
Professor of Pediatrics Manuel Carcao from the University of Toronto discussed the unpublished results of the paradigm5 and 6 studies. Both studies monitored the safety and efficacy of N9-GP and were single-arm and open-label.
The paradigm5 study included 25 boys up to 12 years old (median age 7 years), who had already been treated with a FIX product for at least 50 days (i.e., “pre-treated“). The study began in May 2012 and followed participants for approximately 11 years. The paradigm6 study included 50 boys (median age 1 year) with a maximum of 3 days' exposure to FIX products (i.e., “untreated“). Paradigm6 started in July 2014 and ended in October 2022, with a monitoring period of about 8 years.
The genetic profile of patients in both studies was similar. The incidence of missense mutations, which carry a lower risk of inhibitor development, was 40–50%. In 21–24% of individuals, nonsense mutations, associated with a higher risk of inhibitor development, were detected.
In both studies, N9-GP was administered in a prophylactic regimen of 40 IU/kg intravenously once a week. In case of bleeding, a dose of 40 IU/kg (or 80 IU/kg for severe bleeding) was administered.
The primary endpoint in both studies was the immunogenicity of the product (i.e., incidence of inhibitors). While no cases of inhibitors were detected in the paradigm5 study as expected, in the paradigm6 study with untreated patients, inhibitors developed in 4 out of 50 participants (8%). This incidence was anticipated and is similar to the situation with other FIX products. The patients with inhibitors had a higher-risk genetic profile: 3 were carriers of nonsense mutations, and the fourth was a carrier of a large deletion in the FIX gene.
Secondarily, both studies evaluated the safety and efficacy of the product for long-term prophylaxis and bleed treatment. Both studies demonstrated excellent efficacy of the prophylactic treatment with satisfactorily high trough levels of FIX (average values were 18.1% in paradigm5 and 15.6% in paradigm6). Trough levels slightly increased with the patients' ages. The medication level 30 minutes post-infusion reached 60–70%. Patient adherence to treatment was very high due to the once-weekly administration.
The high efficacy of N9-GP was indicated by low ABR values throughout the monitoring period, being 0.85 in the paradigm5 study and 0.65 in the paradigm6 study. The vast majority of bleeds were treated with a single rescue dose of N9-GP.
Safety profile of N9-GP therapy
The incidence of adverse events (AEs) in both studies did not exceed the expected rate and did not involve unexpected AEs.
Regular monitoring of the safety of the drug showed no accumulation of polyethylene glycol (PEG); plasma levels remained stable throughout the monitoring period.
No negative effects on liver and kidney functions were proven among the patients. Regular neurological assessments (tests evaluating coordination, fine motor skills, cranial nerve function, gait disorders, muscle strength, or muscle tone) and cognitive function assessments were carried out. Results were summarized in the eTHINK project (Evolving Treatment of Haemophilia’s Impact on Neurodevelopment, Intelligence, and other Cognitive Functions) and presented by Helle Host from Novo Nordisk's research division. Among recorded CNS-related AEs, no link to N9-GP administration was found, nor was there a correlation with PEG levels.
The findings of both studies confirmed the excellent efficacy and safety of N9-GP treatment.
MUDr. Eva Havlová
Institute of Clinical Biochemistry and Hematology, Charles University and University Hospital in Pilsen
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