FLT180a, Gene Therapy for Hem B, Sustaining Higher FIX Levels
A single dose of Freeline Therapeutics’ experimental gene therapy FLT180a increased the levels of factor IX (FIX) — the missing clotting protein in hemophilia B — for up to around 3.5 years in nine out of 10 men with moderate-to-severe disease.
That’s according to data from the Phase 1/2 B-AMAZE clinical trial and an extension study, which were presented at a conference last year. Findings have now undergone peer review and been published in The New England Journal of Medicine.
The published study is called “Phase 1–2 Trial of AAVS3 Gene Therapy in Patients with Hemophilia B.”
“The B-AMAZE long-term data continue to support our confidence that a single dose of FLT180a could protect people with hemophilia B from bleeding and the need for lifelong FIX replacement through durable expression of FIX at protective levels,” Pamela Foulds, MD, Freeline’s chief medical officer, said in a company press release.
Hemophilia B is caused by mutations in the F9 gene that affect the production of the FIX clotting protein. FLT180a uses a modified and harmless virus, called AAVS3, to deliver a working version of this gene to liver cells, the body’s main producers of blood clotting factors.
As such, a single dose of the therapy is expected to help restore FIX levels, and reduce bleedings and the need for use of replacement therapies.
B-AMAZE trial and extension study findings
The Phase 1/2 B-AMAZE trial (NCT03369444) was designed to identify a dose of FLT180a that could keep FIX activity within the normal range (50–150%) in men with moderate-to-severe hemophilia B, reflected by FIX activity levels of 2% or lower.
The study enrolled 10 patients (nine Caucasians and one Asian) whose ages at study’s screening ranged from 25 to 67. All completed the six-month trial and entered into a long-term follow-up study (NCT03641703), which is evaluating the therapy’s safety and efficacy for up to 15 years.
Participants were given a single infusion of FLT180a at one of four doses, ranging from 3.84 hundred billion to 1.28 trillion vector genomes per kilogram (vg/kg). They also received an immunosuppressive regimen (glucocorticoids with or without tacrolimus) to prevent an immune reaction against the viral vector.
Newly published results, at a data cutoff date of Sept. 20, 2021, concerned a median follow-up period of 27.2 months (or just over two years). Participants were followed for a minimum of 19.1 months (about 1.5 years) and a maximum of 42.4 months (over 3.5 years).
A dose-dependent increase in FIX levels was seen, and these levels were sustained over time in nine of the 10 men.
Specifically, at last follow-up, five patients had normal FIX levels (range, 51–78%), while three patients had slightly lower levels (range, 23–43%). Notably, one patient given the highest dose had higher-than-normal FIX activity, at 260%.
“Our results confirm that gene therapy with FLT180a can result in factor IX levels in the normal range with relatively low vector doses,” the researchers wrote.
The one man who did not show a long-term FIX increase experienced an initial raise in the clotting factor levels. However, about five months after dosing, he showed an increase in a marker of liver damage, presumably due to an immune response against the viral carrier, and his FIX levels fell back to below 2% in the following months.
He returned to using preventive FIX replacement therapy.
This event was “unanticipated owing to the length of time since the FLT180a infusion, which led to delayed recognition,” the researchers wrote, noting that more monitoring was given subsequent patients in the trial.
In addition, among the 10 patients, the mean yearly bleeding rate dropped from 2.93 bleeds per year before treatment with FLT180a to 0.71 bleeds per year after the gene therapy.
The use of FIX replacement therapies also decreased from a pre-treatment mean of 226,026 international units per year to a post-treatment mean of 9,723 international units per year.
Continuing to test gene therapy’s potential
“The B-AMAZE long-term data add to the growing body of evidence that gene therapy has the potential to free patients from the challenges of having to adhere to lifelong therapy or could provide treatment where none exists today,” said Amit Nathwani, MD, PhD, a study co-author and a co-founder and board member of Freeline.
Nathwani is also a professor of hematology at University College London Cancer Institute.
Temporary increases in the liver damage marker — a liver enzyme called aminotransferase — were the most common adverse event associated with FLT180a.
“Late increases in aminotransferase levels occurred in patients who had received prolonged tacrolimus beyond the glucocorticoid taper,” the researchers wrote.
A serious blood clot-related adverse event occurred in the man showing higher-than-normal FIX levels and was resolved with anti-clotting medication.
No patient experienced infusion reactions or developed antibodies against the delivered FIX. The safety profile of the immunosuppressive regimen was generally in line with the known profile of those medications.
“Despite the high level of sustained factor IX expression, unexpected late episodes of increases in liver aminotransferase levels and decreases in factor IX levels were observed,” the researchers wrote.
“Work is ongoing to refine the immunosuppression regimen with the goal of reducing [viral carrier-related] immune responses in the early period after treatment and enabling durable factor IX expression without late decreases in values,” the team added.
Freeline launched a dose-confirmation Phase 1/2 trial, called B-LIEVE (NCT05164471), to further test FLT180a in up to nine men with moderate-to-severe hemophilia B. The trial may still be recruiting eligible patients at Children’s Hospital of Los Angeles in California.
Preliminary data from the first three participants, treated with a dose of 7.7 hundred billion vg/kg — considered FLT180a’s optimal dose based on B-AMAZE data — showed that all achieved normal FIX levels more than one month after dosing.
“In addition to the promise FLT180a holds for people with hemophilia B, these long-term data demonstrate the potential of our proprietary AAVS3 capsid to enable strong and durable gene expression at low vector doses to effectively treat debilitating inherited diseases with a good safety profile,” said Michael Parini, Freeline’s CEO.