Background

Hemophilia B is a rare genetic disorder caused by a deficiency in clotting Factor IX (FIX), which is synthesized in the liver. Depending on the level of deficiency, spontaneous bleeding into joints or muscles occurs repeatedly, leading to chronic arthropathy and functional impairment. Until now, the standard treatment has relied on lifelong prophylaxis involving intravenous injections of clotting factor concentrates 1–2 times per week. Frequent venipunctures cause cumulative vascular damage and reduce medication adherence, tethering adolescent patients—who are otherwise active—to their needles. This situation has acted as a heavy burden on their daily lives, impeding both their academic pursuits and social activities.

In adult patient groups, the landscape of treatment has changed rapidly with the commercialization of Adeno-Associated Virus (AAV) vector-based gene therapies. This is thanks to the development of a drug incorporating the Padua variant gene, which exhibits 5–8 times higher clotting activity than the wild-type protein. This was a turning point, inducing long-term hemostatic effects with a single intravenous injection, significantly reducing the burden of unit-dose clotting factor supplementation.

Conversely, adolescent patients were excluded from these benefits. This was due to the high risk of dilution of the AAV genome—which exists in an episomal form rather than being inserted into chromosomes—during the process of hepatocyte proliferation associated with physical growth. Concerns that cytotoxic T cells, which respond to the viral capsid via immune mechanisms distinct from those in adults, could be activated and cause liver toxicity also hindered progress. Therefore, there was an urgent need for clinical evaluations to verify whether safety and efficacy in growing adolescents are equivalent to those in adults.

Key Findings

In a multicenter, single-arm, phase 1 clinical trial involving medical institutions in China, researchers recruited 11 adolescent patients with severe to moderate hemophilia B, aged 12 to 18 years. All patients' baseline Factor IX Coagulant Activity (FIX:C) was 2 IU/dl or less, leaving them exposed to spontaneous bleeding. The researchers administered a single intravenous dose of BBM-H901, an AAV gene therapy carrying the Padua variant, at a dose of 5×10^12 vector genomes per kilogram of body weight (vg/kg), and conducted follow-up observations for 52 weeks.

Clinical results showed no dose-limiting toxicity (DLT) following drug administration, and overall tolerability was good. Major adverse events were mild, including elevated white blood cell and neutrophil counts and skin rashes due to prophylactic corticosteroid administration. One patient showed an increase in liver enzyme levels (ALT/AST), but returned to the normal range within 4 weeks following immunosuppressive treatment.

The efficacy indicators were comparable to adult clinical results. At week 52 post-administration, the average FIX coagulant activity of the patients soared to 41.8 (±30.1) IU/dl, achieving near-normal hemostatic capability. All 11 participating patients achieved the milestone of completely discontinuing the regular administration of exogenous clotting factor injections.

The reduction in bleeding frequency was also striking. The average Annualized Bleeding Rate (ABR), which was 13.9 times per year before treatment, plummeted to 0.5 times after administration. With a 96.4% reduction in bleeding frequency, the risk of repeated bleeding that causes joint damage during growth was virtually eliminated.

Implications and Outlook

These clinical results refute academic concerns with scientific data that the therapeutic gene would be prematurely lost due to hepatocyte division during the growth period. It provides the first clinical evidence that stable expression of blood clotting factors can be maintained with a single AAV administration even in the adolescent patient group. It is considered to pave the way for blocking joint damage from childhood through early gene therapy.

Follow-up tasks are also clear. Considering the characteristic of adolescent patients having a longer life expectancy than adults, long-term follow-up studies to determine whether expression efficacy is maintained for 5–10 years or more are essential. Since the current AAV platform does not allow for re-administration due to the formation of neutralizing antibodies in the body, alternatives must also be devised in case expression levels decrease over time.

High treatment costs and the criteria for screening anti-AAV antibodies prior to administration remain barriers to overcome. Despite these challenges, its clinical value—fundamentally improving quality of life in adolescents and preventing joint deformity—is regarded as a decisive turning point that expands the landscape of hemophilia treatment.