Factor IX Levels Normal After Gene Therapy for First 3 Patients in Trial

Marisa Wexler, MS avatar

by Marisa Wexler, MS |

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The first three participants in the B-LIEVE trial all have factor IX (FIX) levels within the normal range more than one month after being treated with FLT180a, Freeline’s experimental gene therapy for hemophilia B, according to the company.

“The initial data show that FLT180a provides rapid and consistent elevations in FIX to normal levels, which can prevent bleeding and the need for regular FIX replacement in people with hemophilia B,” Pamela Foulds, MD, chief medical officer of Freeline, said in a press release.

Interim data from the trial were presented at the International Society on Thrombosis and Haemostasis (ISTH) Congress, held this month in London, in a poster titled, “Results from B-LIEVE, a Phase 1/2 Dose-Confirmation Study of FLT180a AAV Gene Therapy in Patients with Hemophilia B.”

Hemophilia B is caused by mutations in the gene that provides instructions for making the clotting protein factor IX, known FIX. FLT180a is designed to deliver a healthy version of this gene to cells in the liver — the main producers of clotting factors in the body — thus restoring the production of functional FIX. The therapy delivers its genetic payload by way of a specially engineered viral vector.

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A previous Phase 1/2 trial called B-AMAZE (NCT03369444) evaluated several doses of FLT180a. Results suggested that the experimental gene therapy could normalize FIX levels for years after dosing, and indicated the optimum dosage to be 7.7e11 (7.7 hundred billion) vectors genomes per kilogram of body weight (vg/kg).

B-lieve trial still enrolling men, ages 18–65

The B-LIEVE trial (NCT05164471), launched in December 2021, was designed to confirm this dosage in preparation for a planned pivotal Phase 3 trial. Up to nine participants are to be given an immune-suppressing regimen — corticosteroids plus the anti-rejection medication tacrolimus — around the time they receive FLT180a to prevent an immune reaction against the viral vector.

The first participant was dosed earlier this year. B-LIEVE is open to men, ages 18–65, with FIX activity 2% of normal or lower; participants are being recruited at a study site in Los Angeles.

The ISTH presentation included data from the first three participants, ages 24, 22, and 51. As of data-cutoff in May, these men had been followed for 77, 56, and 36 days, respectively.

All three patients had normal levels of factor IX at the end of the cutoff date. Specifically, patient 1 had levels of 93 international units per deciliter (IU/dL) — the normal range is 50 to 150 IU/dL. The levels for patient 2 were 92 IU/dL, and those for patient 3 were 80 IU/dL.

Each patient also stopped all prior prophylactic (preventive) treatments without any issues.

The experimental therapy has so far been well-tolerated, with no serious adverse events (side effects) reported. Most of the reported adverse events were attributable to the immune-suppressing regimen. The older participant reported four mild events deemed possibly related to FLT180a, which included feeling hot, dizziness, eye pain, and headache.

A second group, also including three patients, was dosed in June with the same dosage of FLT180a and the same immune-suppressing regimen.

According to Freeline, available data from after the cutoff date of this analysis continue to show factor IX levels within the normal range, with no patients experiencing bleeding or requiring FIX replacement therapy. However, two patients have reported a decrease in factor IX levels concurrent with an increase in markers of liver injury.

“Emerging data suggest that while FIX expression was maintained at protective levels, a further refined immune management regimen may be required to avoid mild and transient transaminitis [unusually high levels of certain enzymes] and to sustain FIX levels in the normal range,” Foulds said, adding, “Potential adjustments in cohort [group] two and forthcoming results from that cohort will help us interpret this further.”

In addition to its hemophilia B treatment candidate, Freeline is developing gene therapies for Gaucher disease and Fabry disease, both of which are lysosomal storage disorders — genetic conditions that cause problems with cellular recycling machinery, leading to the toxic buildup of certain molecules inside cells.

“While we continue to believe FLT180a has the potential to deliver a best-in-class gene therapy for people with hemophilia B, the availability of other treatment options and the need to prioritize our valuable resources dictate that we evaluate strategic options for FLT180a,” said Michael Parini, Freeline’s CEO.

“These include, but are not limited to, seeking a partner that would enable the continuation of FLT180a through Phase 3 development,” he said.

Parini noted that the company’s Gaucher and Fabry gene therapies have the potential to be the first such treatments for these diseases.

“Our strategy is to advance gene therapy programs that have the potential to deliver best-in-class or first-in-class treatments,” said Parini. “With two other promising programs in Fabry disease and Gaucher disease in the clinic, … we will continue to focus our attention and resources on those programs that offer the highest value for patients and Freeline’s shareholders.”