Pharmacokinetic-Guided Reduction of Emicizumab in Patients with Congenital Hemophilia a in the Netherlands: Interim Analysis from the Dosemi Study

Background: While prophylactic emicizumab therapy is highly effective in preventing bleeding in hemophilia A and generally well-tolerated, the high costs impose a significant financial burden on healthcare systems. Several case series have suggested that current bodyweight-based dosing of emicizumab could be safely reduced, providing similar effectiveness at a lower cost.

Aim: Determine whether individualized PK-guided reduced dosing of emicizumab targeting a C_trough emicizumab concentration of 30±5 μg/mL is non-inferior to conventional bodyweight-based dosing in the prevention of bleeding in hemophilia A patients.

Methods: The DosEmi study is an ongoing phase IV, multicenter, prospective, open-label, crossover study comparing 12 months of conventional dosing of emicizumab vs 12 months of PK-guided reduced dosing targeting at concentrations of 30±5 μg/mL (ClinicalTrial.gov - NCT06320626). Study participants were recruited from eight Dutch hemophilia treatment centers from September 1^st 2022 onwards.

Eligible participants have severe or moderate congenital hemophilia A (FVIII < 6 IU/mL) with and without FVIII-inhibitors; receiving conventional dosing of emicizumab (according to label of 6 mg/kg/4 weeks at varying intervals) for a duration of ≥ 12 months prior to inclusion with good bleeding control, defined as: no spontaneous joint/muscle bleeds in the previous six months and/or a maximum of two treated (traumatic) bleeds in the previous six months.

Emicizumab concentrations were determined by a validated liquid chromatography-tandem mass spectrometry method after 12 months on conventional dosing, only patients with an emicizumab trough levels of ≥ 40 μg/mL were eligible for dose reduction. Patients with emicizumab trough levels of 25-39 μg/mL continued their current dose regimen and were followed observationally for 12 months. Patients with emicizumab trough levels of < 25 μg/mL were adjusted in dosing regimen according to local protocol.

The interim analysis was scheduled to compare the proportion of patients without treated bleeds during six months of follow-up on conventional dosing to six months on PK-guided dosing using survival analysis, with a predefined non-inferiority criterion of an absolute risk difference of <16%. Patient characteristics were summarized as numbers (%) and medians with interquartile range (IQR, P25-P75).

Results: On July 1^st 2024, 72 patients were included in the study. Emicizumab concentrations were measured in 30 patients, and the emicizumab dose was reduced in 27 out of 30 patients. The median age of study participants was 52 (IQR 33 - 62) years. All patients had severe hemophilia A, and the majority of patients had no FVIII inhibitors (n=25, 93%).

Overall, the emicizumab dose was decreased from a median of 6 (IQR 5.2 - 6.4) mg/kg/4wks to 3.4 (IQR 2.8 - 3.9) mg/kg/4wks. The median follow up during PK-guided dosing was 4.6 (IQR: 3.2 - 10.5) months, of which 13 patients completed the entire six months on PK-guided dosing.

Bleeding control remained stable over the follow-up period. The proportion of patients without treated bleeds was 76% during conventional dosing versus 71% during the PK-guided dosing (p=0.222). Similar results were observed with regard to the proportion of patients without treated joint bleeds, 82% versus 87% respectively (p=0.609). All bleeds were traumatic except in one patient who developed a spontaneous ultrasound confirmed muscle bleed on PK-guided dosing.

Regarding the safety, no emicizumab related adverse events nor thrombotic events were observed after dose reduction

Conclusion: With an absolute risk difference of +5% for absence of bleeding and -4% for absence of joint bleeding, these preliminary interim results suggest that PK-guided reduced dosing of emicizumab at concentrations of 30±5 μg/mL is non inferior to conventional dosing in preventing bleeding in patients with congenital hemophilia A. The definite results from this prespecified interim analysis evaluating the full six months of PK-guided dosing in 25 adult patients will be available in December 2024.

Cnossen:Roche: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Nordic Pharma: Research Funding, Speakers Bureau; Novartis: Research Funding, Speakers Bureau; Novo Nordisk: Research Funding, Speakers Bureau; CSL Behring: Research Funding, Speakers Bureau; Bayer: Research Funding, Speakers Bureau; Pfizer: Research Funding, Speakers Bureau; Takeda: Research Funding, Speakers Bureau. Moenen:Octapharma: Research Funding; Bayer: Research Funding. Ypma:Novartis: Other: Remuneration as a speaker for conference without personal financial compensation; Johnson & Johnson: Other: Partial reimbursement of conference attendance costs; remuneration as a speaker for conference without personal financial compensation. Coppens:Bayer: Honoraria, Research Funding; European Association for Haemophilia and Allied Disorders (EAHAD): Other: Non-financial conflicts of interest: Member of the gene therapy working group of the European Association for Haemophilia and Allied Disorders (EAHAD); Sobi: Honoraria, Research Funding; F. Hoffman-La Roche: Research Funding; Octapharma: Honoraria; Spark Therapeutics: Honoraria; Novo Nordisk: Research Funding; Pfizer: Honoraria; CSL Behring: Honoraria, Research Funding. Mathôt:Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; CSL Behring: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sobi: Research Funding; CelltrionHC: Research Funding; Merck Sharp & Dohme: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees, Research Funding. Van Beers:Agios Pharmaceuticals, Inc.: Consultancy, Research Funding. Van Vulpen:NovoNordisk: Research Funding; Griffols: Research Funding. Schutgens:Takeda: Research Funding; Sobi: Research Funding; Roche: Research Funding; Octapharma: Research Funding; Novo Nordisk: Research Funding; Novartis: Research Funding; Hemab: Research Funding; CSL Behring: Research Funding; Bayer: Research Funding. Fischer:NovoNordisk: Speakers Bureau; Bayer: Speakers Bureau; Pfizer: Research Funding; NovoNordisk: Research Funding; Bayer: Research Funding; SOBI: Consultancy; NovoNordisk: Consultancy; CSL Behring: Consultancy; Biogen: Consultancy; Bayer: Consultancy; Pfizer: Speakers Bureau.