Oral hemophilia A treatment shows promise in preclinical studies

Inno8, a potential oral treatment to prevent bleeds in people with hemophilia A, appears more potent and long-lasting than currently available injectable treatments in preclinical laboratory and animal studies, a study suggested.

The candidate therapy, being developed by Novo Nordisk, is undergoing clinical testing and has completed its first-in-human dosing evaluation in a Phase 1 clinical trial called VOYAGER1 (NCT06649630).

“Pending further clinical evaluation, Inno8 may represent an advance in biologics development and a potential non-invasive prophylactic [preventative] therapy for individuals with [Hemophilia A],” the researchers wrote.

The study, “Development of Inno8, an orally administered factor VIIIa–mimetic antibody fragment for treatment of hemophilia A,” was published in Blood. All authors are current or former employees of Novo Nordisk, and several are named on granted patents related to the technology.

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Oral alternative

Hemophilia A is caused by a deficiency of factor VIII (FVIII), a protein needed for blood clotting. Treatment to prevent bleeds requires lifelong FVIII replacement therapy via intravenous (into-the-vein) infusions.

Recently, antibodies that mimic activated FVIII (FVIIIa) have allowed less frequent subcutaneous (under-the-skin) administration. Still, oral therapy remains a significant unmet need for people with hemophilia A.

With this in mind, Novo Nordisk is developing Inno8, a single-chain antibody fragment that bridges two clotting factors, FIXa and FX, to mimic FVIIIa.

After generating multiple versions via animal immunizations, the front-running candidate was optimized to boost FVIIIa-mimicking activity by nearly 100-fold. Further changes were made to increase oral bioavailability, the proportion of a drug that reaches the bloodstream, from about 0.02% to 0.19% in rats.

In addition, researchers attached a fatty acid at a specific site to extend its time in the body. In dogs, one specific fatty acid increased the half-life, the time it takes for blood drug levels to decrease by 50%, to over 168 hours after intravenous dosing. In contrast, the unmodified version cleared within 15 minutes.

The team then modified the candidate to lower immunogenicity risk, the potential to provoke an immune response that may lead to antibodies against the therapy. Across successive versions, immune T-cell activation decreased from 8% to 3% and then to 0%.

“These responses were comparable to or lower than those observed with clinical benchmark molecules, which elicited responses in 3-9% of donors,” the researchers wrote.

In lab tests, Inno8 bound weakly to one clotting protein, FX, and more strongly to another, FIXa. The researchers noted that this weak initial binding prevents the drug from making unnecessary connections in the bloodstream at low doses. However, once Inno8 hits cell-like surfaces (phospholipid membranes), its ability to bring the two clotting factors together becomes significantly stronger.

The researchers then tested Inno8’s blood-clotting activity using thrombin generation assays, which measure thrombin, a central clotting enzyme, produced in blood. They also tested it with thromboelastography, which measures clot formation in whole blood.

Inno8 increased thrombin generation in a dose-dependent manner and brought it close to the normal range across all assays. In whole blood, it reduced clot time to normal levels.

To see how Inno8 travels through the body, researchers studied its absorption when administered as an injection or as simple oral tablets in an animal model.

When given directly into the bloodstream, the medication stayed active in the body for a long time, taking about 115 hours (nearly five days) for levels to drop by half. When taken as two 10 mg tablets, about 0.2% of the medicine entered the bloodstream. Tests confirmed that the drug remained fully active after being absorbed. Furthermore, taking Inno8 once daily as a 35 mg tablet allowed the medication to steadily build up to effective levels over time.

These findings support “Inno8 as a promising candidate for oral [Hemophilia A] prophylaxis,” the researchers wrote, adding that clinical studies evaluating the treatment’s safety and efficacy will show whether these preclinical findings translate into clinical benefit for individuals with hemophilia A.