A single dose of the experimental gene therapy FLT180a can safely maintain the activity levels of factor IX (FIX) within a normal range for nearly three years, effectively preventing bleeds and the need for replacement therapies in patients with hemophilia B, according to updated data from a Phase 1/2 trial.
“These updated data support the potential for our FLT180a gene therapy product candidate for hemophilia B to provide a functional cure with FIX activity in the normal range,” Theresa Heggie, CEO of Freeline, the company developing FLT180a, said in a press release.
The company recently completed an End of Phase 2 meeting with the U.S. Food and Drug Administration (FDA) to discuss the next steps in FLT180a’s development program. Based on feedback from the agency, Freeline is now anticipating the launch of a pivotal Phase 2b/3 trial in the second half of 2021 to confirm FLT180a’s safety and effectiveness. If positive, data from this study may support the therapy’s approval in the country.
“We look forward to continued progress of our FLT180a program as we work towards achieving our mission of providing functional cures for patients with hemophilia B, enabling them to lead unconstrained, active lives, without fear of spontaneous or trauma-related bleeding events,” Heggie said.
FLT180a is an investigational gene therapy that uses AAVS3, Freeline’s proprietary adeno-associated virus (AAV) protein shell, or capsid, to deliver a functional version of F9, the gene that encodes FIX and is defective in people with hemophilia B, to liver cells.
A Phase 1/2 trial, called B-AMAZE (NCT03369444), is assessing four single doses — 4.5e11 vector genomes per kilogram (vg/kg) in group 1, 1.5e12 vg/kg (group 2), 7.5e11 vg/kg (group 3), and 9.75e11 vg/kg (group 4) — of FLT180a in adult men with moderate to severe hemophilia B, meaning FIX activity of 2% or less.
In addition to safety, B-AMAZE also aims to assess FLT180a’s efficacy at normalizing the activity levels of FIX (50%–150% of what would be considered normal) and lowering the frequency of bleeding episodes. These outcomes were to be evaluated until week 26 (six months) post-dosing.
Previous data from the first eight men treated in the study indicated that when given at a dose of 9.75e11 vg/kg, FLT180a was able to increase and maintain FIX activity levels within a normal range.
More recently, data from the 10 men dosed in the trial suggested that doses ranging between 7.5e11 to 9.75e11 vg/kg were more likely to lead to sustained increases in FIX activity levels in these patients.
Now, Freeline announced six-month follow-up data from all 10 men, who have enrolled in a long-term extension study (NCT03641703) to continue being followed for 15 years.
Safety assessments indicated that FLT180a did not cause any infusion or allergic reactions. Temporary transaminitis (high levels of liver enzymes) was the most common serious side effect.
Long-term follow-up data were available for the two men in group 1 who received FLT180a at a dose of 4.5e11 vg/kg. At week 26, their FIX activity levels were at a mean of 45%, and remained stable (44%) at week 133 (about 2.5 years).
The two men from group 2, who received the therapy at a dose of 1.5e12 vg/kg, saw their FIX activity levels rise beyond the normal range, at a mean of 176% at week 26.
In the two patients from group 3, who received FLT180a at a dose of 7.5e11 vg/kg, FIX activity levels were at a mean 36% at week 26 and 32% at week 52 (one year). These values were higher in the patient who did not experience transaminitis, whose FIX activity levels reached 64% after six months, and remained at 63% after one year.
In turn, the four men in group 4, who received a dose of 9.75e11 vg/kg, had a mean FIX activity of 142% six months following dosing. Yet again, the three men in this group who did not have transaminitis attained slightly higher activity levels at week 26 (mean of 171%). Three patients in this group currently have normal FIX activity levels and one is in the upper end of mild hemophilia.
Apart from a patient in group 3 whose FIX activity levels severely dropped following an episode of transaminitis, none of the participants required replacement therapy following treatment with FLT180a.
According to the researchers, these findings are in agreement with previous data and suggest that doses ranging between 7.5e11 and 9.75e11 vg/kg are the most suitable to allow patients with moderate to severe hemophilia B to attain normal FIX activity levels over long periods of time. This is also the dose range that has been selected to be given to patients participating in an upcoming Phase 2b/3 trial of FLT180a.
Trial investigators also found that a preventive regimen of immunosuppressants consisting of prednisone accompanied by a short course of tacrolimus seemed to lower the risk of transaminitis and the loss of FIX activity in these patients.
“We are encouraged by our long-term follow up data that show, now out to nearly three years, durable FIX expression in treated patients,” said Julie Krop, MD, chief medical officer of Freeline. “In addition to this notable durability, we have selected a dose for our pivotal Phase 2b/3 study that we believe will deliver FIX activity consistently in the normal range, and an immune management regimen that balances the need for the development of immune tolerance with the prevention of transaminitis, in order to preserve expression levels.”
The Phase 2b portion of the upcoming trial will aim to confirm the dose that will then be used in the Phase 3 part.
Freeline then plans to request the therapy be given accelerated approval by the FDA, provided six-month data demonstrate that FLT180a has a strong effect at raising FIX activity levels in around 20 participants. The company also plans to submit data showing a correlation between FIX activity levels at six months post-dosing and annual bleed frequency in a subset of these patients.
This trial will enroll up to 30 more patients to generate data on annual bleed frequency that will potentially support the therapy’s full approval.
Enrollment is ongoing in ECLIPSE (NCT04272554), a six-month run-in study in Australia to gather data on patients’ FIX activity levels, bleed frequency, and eligibility for gene therapy clinical trials.
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