Freeling Published Positive Results from Phase 1/2 of Its Hemophilia B Gene Therapy

Freeline Therapeutics published positive data that expand upon previously announced long-term follow-up data for up to 3.5 years from the phase 1/2 dose-finding trial of the company’s AAVS3 gene therapy candidate, FLT180a, for people with hemophilia B, a debilitating inherited bleeding disorder caused by a deficiency in coagulation factor IX.

The results, published in the New England Journal of Medicine, showed all patients had dose-dependent increases in factor IX (FIX) levels following treatment with FLT180a. Nine of 10 patients had sustained FIX activity at a median follow-up of 27.2 (19.1-42.4) months.

Hemophilia B is a rare, debilitating, hereditary bleeding disorder caused by a defect in the gene encoding coagulation factor IX (FIX) present on the X chromosome. Hemophilia B mainly affects boys and men; however, women who carry an affected copy of the coagulation factor gene may also experience symptoms. Hemophilia B is classified as mild, moderate or severe, depending on the level of FIX in the blood, and is diagnosed through blood tests.

Freeline’s FLT180a candidate uses an AAVS3 capsid rationally designed for effective targeting and transduction of liver cells and containing an expression cassette encoding a gain of function Padua variant of human factor IX. FLT180a has been studied in B-AMAZE, a phase 1/2 dose-finding trial with the goal of normalizing FIX activity in patients with moderately severe and severe hemophilia B. Patients treated in B-AMAZE are being followed in a long-term follow-up study. A phase 1/2 dose-confirmation trial of FLT180a called B-LIEVE to finalize a dose for a phase 3 pivotal trial is in progress.

B-AMAZE was a multicenter, open-label, single-dose phase 1/2 trial of FLT180a in 10 adult men (≥18 years) with severe (FIX activity <1 percent) or moderately severe (FIX activity 1-2 percent with severe bleeding phenotype) hemophilia B. All patients tested negative for AAVS3 neutralizing antibodies prior to enrolling in the trial. The primary endpoints were safety, as assessed by adverse events, and efficacy, as assessed by FIX levels at Week 26. Secondary endpoints included changes in annualized bleeding rates and FIX concentrate consumption, development of FIX inhibitors, and clearance of viral genomes.

Four dose levels were assessed in an ascending/descending adaptive design. Prophylactic immune management consisted of prednisolone with or without tacrolimus. Increases in liver transaminases were treated with prednisolone, tacrolimus, and IV methylprednisolone. Patients were followed for 26 weeks before enrolling in ongoing long-term follow up with the objective to assess safety and durability of FIX normalization for 15 years.

“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,” said Pamela Foulds, chief medical officer of Freeline.

At the last follow up, five patients had FIX levels in the normal range (51-78 percent), three patients had levels ranging from 23 percent to 43 percent, and one high-dose patient was at 260 percent.

The mean annualized bleeding rate across all patients decreased from 2.93 (0-7.33) events/year at baseline to 0.71 (0-1.7) events/year after treatment with FLT180a.

Treatment was generally well tolerated, with transient transaminitis being the most common FLT180a-related adverse event (AE). No patient discontinued infusion or withdrew from the study. No infusion reactions occurred, and no inhibitors to FIX were detected. AEs related to immune management were consistent with the known safety profiles of corticosteroids and tacrolimus.

“In addition to the promise FLT180a holds for people with hemophilia B,” said Michael Parini, CEO of Freeline, “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.”

Author: Rare Daily Staff