BBM-H901, Gene Therapy for Hem B, Shows Efficacy at 1 Year in Pilot Trial

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by Steve Bryson, PhD |

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The gene therapy BBM-H901 increased factor IX activity in 10 men with moderate to severe hemophilia B, while reducing bleeds and the use of FIX replacement therapy over one year, according to results of a pilot Phase 1 trial.

“The study was the first clinical trial conducted by Belief BioMed in China,” Jane Zheng, PhD, CEO of Belief BioMed, the therapy’s developer, said in a press release. “We are very proud to introduce BBM-H901, which is the first intravenously delivered gene therapy drug for hemophilia B in China and the first example of systemic gene therapy for rare diseases in China.”

Findings were reported in the study, “Safety and activity of an engineered, liver-tropic adeno-associated virus vector expressing a hyperactive Padua factor IX administered with prophylactic glucocorticoids in patients with haemophilia B: a single-centre, single-arm, phase 1, pilot trial,” published in The Lancet Haematology.

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In hemophilia B, mutations in the F9 gene lead to a lack or production of a defective version of the blood clotting protein factor IV (FIX), resulting in uncontrolled and prolonged bleeds. Standard treatment is replacement therapy, in which the missing FIX protein is infused into patients to avoid or stop bleeds.

BBM-H901 aims to restore FIX production by delivering a functioning copy of F9 packaged in a modified, harmless adeno-associated virus (AAV) to liver cells, where blood clotting factors are made.

The open-label Phase 1 trial (NCT04135300) evaluated the safety and activity of a single intravenous (into-the-vein) infusion of BBM-H901 in 10 adult men in China.

Eligible participants had a pre-treatment FIX activity of less than 2 international units per deciliter of blood (UI/dL), no antibodies against the FIX protein, and low levels of antibodies targeting the AAV. Patients received regular doses of the immunosuppressant prednisone for one week, followed by a single dose of BBM-H901 at 5×1012 vector genomes per kilogram of weight (vg/kg).

Participants were monitored for treatment-related side effects, liver toxicity, and the development of antibodies against AAV. FIX activity, bleeding rates, and replacement therapy use were also evaluated.

Within the first week of infusion, mean FIX activity reached 57.1 IU/dL, peaking at 64.1 IU/dL at a median of five weeks. The mean increase in FIX activity over the median follow-up period of 58 weeks (just over one year) was 36.9 IU/dL.

The median annualized bleeding rate dropped from 12 to zero, the median number of target joints decreased from 1.5 to zero, while the median number of FIX replacement therapy infusions fell from 53.5 to zero. Of note, target joints are joints where bleeds occur frequently.

There were no reports of serious or severe adverse events. One patient had a fever and another elevated levels of a liver enzyme, a sign of liver toxicity. Although no anti-FIX antibodies were seen, all developed antibodies against the AAV after the infusion.

“This pilot study suggests that liver-tropic BBM-H901 is safe [one] year after infusion,” the researchers wrote. “Vector derived FIX:C concentration is sufficiently high to prevent bleeding events and minimize the need for replacement therapy in small populations with hemophilia B.”

Its findings “support further study,” they added.

After the one-year of follow-up, participants were given the option to enroll in an extension study evaluating the safety of BBM-H901 for up to five years.

“The BBM-H901 study is the first clinical study in China and even Asia to utilize liver-targeted AAV vectors for the treatment of hemophilia B,” said Zhang Lei, MD, a professor at the Chinese Academy of Medical Sciences.

“The safety and long-term effectiveness of this treatment strategy have been well demonstrated with significant relief of associated complications,” added Lei, who is also vice director of the Institute of Hematology and Blood Diseases Hospital at the Chinese Academy.