High Dose of Gene Therapy for Hemophilia B Normalizing FIX Levels, Early Trial Data Show

When administered at a high dose, a gene therapy for hemophilia B known as FLT180a seems able to restore the activity of clotting factor IX (FIX) within a normal range in men with moderate-to-severe disease, early data from Phase 1/2 trial show.

The findings were announced in an oral presentation, “Phase 1/2 interim data from B-AMAZE study of adeno associated virus (AAV) gene therapy (FLT180a) confirms progress towards achieving Factor IX levels in the normal range for patients with severe or moderately severe haemophilia B,” at the 13th European Association for Haemophilia and Allied Disorder (EAHAD) in the Netherlands, the therapy’s developer, Freeline, announced in a press release.

Hemophilia B is caused by the lack of a functional FIX as a result of mutations in the gene encoding it, called F9. The idea behind gene therapies for this disorder is to provide patient cells with a non-mutated version of the gene responsible for working to produce the clotting factor — in this case F9 — allowing the body to make whatever factor is missing.

FLT180a uses a capsid (protein shell) from a harmless adeno-associated virus (AAV) that can infect human cells. AAVS3, Freeline’s proprietary capsid, is designed to specifically target and deliver the correct version of F9 to a patient’s liver cells, which are responsible for the production of clotting factors.

The experimental gene therapy is currently being tested in an open-label Phase 1/2 trial (NCT03369444) called B-AMAZE, which is evaluating the safety and efficacy of single, ascending doses of FLT180a in adult males with moderate-to-severe hemophilia B.

The study, being carried out in collaboration with University College London (UCL), aims to determine the optimal dose at which FLT180a would ensure that patients achieve normal FIX activity and no longer require FIX concentrates. B-AMAZE is currently recruiting participants in the U.K. Additional information can be found here.

Previously findings in the first two men dosed in the trial demonstrated that FLT180a was able to increase FIX levels and keep them stable over a period of one year. At the lowest dose tested (4.5×10¹¹ vector genomes (vg)/kg), FIX levels rose to about 40% of what is considered normal.

The recently presented data covers the first eight patients treated in the trial. Participants received one of four doses of FLT180a, with two people in each dose group.

These data suggest that, when administered at the fourth and likely highest dose (9.75×10¹¹ vg/kg), FLT180a may be able to increase and maintain FIX activity within a normal range (50-150%).

“The data presented at EAHAD are promising, with 8 patients treated in a 4-dose cohort study, and the early data for the fourth dose cohort of 9.75e11 vg/kg suggests the potential to deliver FIX activity between 70-150%, the upper part of the normal range,” Chris Hollowood, Freeline’s executive chairmen, said in a press release.

“These data confirm the progress we are making towards achieving Factor IX levels in the normal range for patients with severe or moderately severe Haemophilia B,” said Amit Nathwani, MD, founder and chief scientific officer of Freeline.

“The progress also demonstrates the efficiency of our next generation AAV capsid,” Nathwani added.

People taking part in this and other trials into FLT180a in Europe or the U.S. are being invited to enroll in a long-term safety and durability study (NCT03641703). Sponsored by Freeline, this trial will follow up to 50 people for 15 years post-treatment, with participants undergoing regular physical exams, blood tests, and liver ultrasounds.

In addition to FLT180a, the company is developing FLT210, a similar AAVS3-based gene therapy that aims to treat hemophilia A. FLT210 is currently in preclinical testing.