Subcutaneous OCTA101 Trial in Severe Hemophilia A Halted Due to Safety Concerns

In a phase 1/2 trial assessing subcutaneous (SC) OCTA101 in patients with severe hemophilia A, promising results in pharmacokinetics (PK) and efficacy were overshadowed by safety concerns. The trial was terminated due to an unexpectedly high incidence of factor VIII (FVIII) inhibitors, prompting the discontinuation of OCTA101 clinical development.

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Patients with severe hemophilia A often face challenges with regular intravenous (IV) FVIII administration, prompting the exploration of alternative treatment options. SC FVIII administration presents a potential solution, offering greater convenience and avoiding the complications associated with venous access. This led to the initiation of a single-center, prospective, open-label, phase 1/2 study (NCT04046848) to evaluate the safety, PK, bioavailability, and efficacy of SC OCTA101—a recombinant FVIII with a recombinant von Willebrand factor fragment dimer.

The primary objective of the study was to assess the safety of OCTA101, including immunogenicity. Secondary objectives included evaluations of PK, bioavailability, and the efficacy of prophylaxis.

FVIII inhibitors, rarely seen in prior FVIII-treated patients, emerged more frequently with SC OCTA101, suggesting an increased risk associated with this route, according to the study published in Haemophilia. Similar inhibitor development occurred with another SC FVIII product (N8-GP), raising concerns about SC administration's general immunogenicity.

FVIII inhibitors to OCTA101 appeared after 35–180 exposure days, indicating a delayed immune response, akin to observations in the SC N8-GP study. In contrast, IV FVIII inhibitors typically emerge within 20 exposure days, the investigators stated.

The study included male patients aged 18 years or older with severe hemophilia A who had been previously treated. Thirty patients were enrolled and received treatment with OCTA101. The study employed daily prophylaxis with varying doses of 40 to 60 IU/kg and 12.5 IU/kg OCTA101.

Despite promising initial results, the trial had a setback as FVIII inhibitors developed in 16.7% (5 out of 30) of patients during daily prophylaxis. Three cases occurred at the 40 to 60 IU/kg dose, while 2 cases occurred at the 12.5 IU/kg dose, leading to the premature termination of the trial.

Pharmacokinetic analysis revealed that OCTA101 exhibited a 2.5-fold longer terminal half-life compared with IV rFVIII, suggesting potential benefits in terms of dosing frequency. The bioavailability of OCTA101 was reported to be 16.6%.

Efficacy data collected until the termination of the study indicated that daily prophylaxis with 40 to 60 IU/kg OCTA101 was effective in managing hemophilia A in the absence of FVIII inhibitors.

Despite promising pharmacokinetic and efficacy results, the trial was terminated due to the incidence of FVIII inhibitors, investigators wrote. The development of inhibitors at 2 different dose levels suggests a potential correlation with the subcutaneous route of administration. This unexpected outcome highlights the complexities associated with the development of novel treatment modalities and emphasizes the need for further research to address the immunogenicity challenges associated with subcutaneous FVIII administration in patients with hemophilia A.

Reference

Lissitchkov, T, Jansen, M, Bichler, J, Knaub, S. Safety, pharmacokinetics and efficacy of a subcutaneous recombinant FVIII (OCTA101) in adult patients with severe haemophilia A. Haemophilia. 2023;1-7. doi:10.1111/hae.14898