FLT180a for Hemophilia B Keeps Normal Factor IX Levels for 3+ Years
In a Phase 1/2 dose-finding study called B-AMAZE, FLT180a gene therapy from Freeline Therapeutics brought about sustained levels of factor IX, the clotting factor that is missing in people with hemophilia B, and this translated into fewer bleeds each year.
Levels of factor IX within the normal range were achieved with relatively low doses of FLT180a and maintained for more than three years.
The results of the study, “Factor IX Expression within the Normal Range Prevents Spontaneous Bleeds Requiring Treatment Following FLT180a Gene Therapy in Patients with Severe Hemophilia B: Long-Term Follow-Up Study of the B-Amaze Program,” were presented in a poster at the 63rd American Society of Hematology (ASH) Annual Meeting and Exposition. The meeting was held on Dec. 11–14 at the Georgia World Congress Center in Atlanta.
“The data presented today at ASH demonstrate that FLT180a gene therapy has the potential to deliver a durable, functional cure for hemophilia B,” Michael Parini, Freeline CEO, said in a press release.
“Patients in the first cohort experienced sustained expression of factor IX out to 3.5 years following treatment with FLT180a. The data from our B-AMAZE study also informed our B-LIEVE dose-confirmation study, enabling us to identify a dose and prophylactic [preventive] immune management regimen that we believe can get and keep hemophilia B patients in the normal range of factor IX expression,” Parini added.
The Phase 1/2 B-LIEVE dose-confirmation study was launched in one trial site on Dec. 6, three months ahead of schedule, and is expected to yield interim data in mid-2022.
“We are excited to get this trial started and completed to enable a Phase 3 pivotal study. Enrollment in the … run-in study for the B-LIEVE trial has proceeded more quickly than expected and, as a result, we believe we have identified a sufficient number of patients to fully enroll the B-LIEVE trial,” Parini said.
FLT180a works by delivering a healthy copy of the gene encoding factor IX to liver cells. The gene is carried in a harmless vector that the company has derived from a naturally occurring virus called adeno-associated virus (AAV).
The 26-week B-AMAZE study (NCT03369444) was designed to identify a dose of FLT180a that maintains factor IX activity within the normal range (50–150%) in people with hemophilia B. Its long-term follow-up study (NCT03641703) is following up the patients who entered the B-AMAZE study for up to 15 years after they have received FLT180a.
Ten patients were treated in the B-AMAZE study with a single dose of FLT180a and followed up for a median of 27.2 months (about 2.2 years) and a maximum of 42 months (3.5 years).
Four different doses of FLT180a were tested, and factor IX activity increased as the dose increased. In nine patients (90%), FLT180a — even at the lowest dose — resulted in sustained levels of factor IX. In five patients (50%), levels of factor IX were within the normal range.
“A gene therapy that could produce sustained FIX [factor IX] levels in the normal range (50–150%) would be expected to protect patients from spontaneous, traumatic and surgical bleeding, prevent microbleeds, and eliminate activity restrictions and the need for treatment with supplemental FIX,” the researchers wrote.
Indeed, administration of exogenous (outside the body) factor IX decreased from a median 201,333 units per year before FLT180a gene therapy to zero after therapy. Moreover, no spontaneous bleeds required supplemental factor IX in patients who maintained factor IX levels above 50%.
“Across the nine of 10 patients with sustained FIX expression after FLT180a treatment, [the] only one [who] reported traumatic bleed was treated with FIX replacement; it occurred in [a patient] who had an endogenous FIX level of 57% at the time,” the researchers wrote.
The researchers also suggest that a dose of 7.7e11 (7.7 hundred billion) vectors genomes per kilogram of body weight (vg/kg), coupled with a short course of preventive treatment, has the potential to achieve durable factor IX activity within the normal range.
This should be enough to “prevent spontaneous bleeds and normalize hemostasis in the event of traumatic bleeds,” they wrote.
FLT180a was generally well-tolerated, and there were no hypersensitivity or allergic reactions during or shortly after infusion of FLT180a. The most common side effect was a temporary increase in the levels of certain liver enzymes, as reported previously.