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Hemophilia B Gene Therapy Shows Long-Term Ability to Reduce FIX Consumption

Most patients treated with FLT180a had elevated FIX levels over 2 years after treatment.

New data from the phase 1/2 B-AMAZE trial (NCT03369444) and its long-term follow-up study (NCT03641703) published in New England Journal of Medicine further supports FLT180a’s (verbrinacogene setparvovec; Freeline Therapeutics) ability to yield sustained factor IX (FIX) levels in patients with hemophilia B.1

“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, chief medical officer, Freeline, said in a statement.1

As of the cutoff date of September 20, 2021, 9 out of 10 patients (90%) dosed with FLT180 had sustained FIX activity at a median follow-up of 27.2 (range, 19.1-42.4) months. As of the last follow-up, 5 patients (50%) had FIX levels in the normal range (51-78), 3 (30%) had levels ranging from 23-43% of normal. One patient (10%) in the high-dose cohort had 260% normal FIX activity.

Additionally, mean annualized bleeding rate (ABR) across all patients decreased from 2.93 events per year (range, 0-7.33) at baseline to 0.71 events per year (range, 0-1.7) after treatment. Mean annualized FIX consumption per patient decreased from 226,026 IU per year (range, 83,263-423,333) at baseline to 9,723 IU per year (0-95,532).

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FLT180a treatment was generally well-tolerated, with mostly mild adverse events (AEs). The most common serious treatment-related AE was transient transaminitis. AEs related to immune management were consistent with the safety profiles of corticosteroids and tacrolimus. No patient discontinued treatment or withdrew from the study. There were no infusion reactions or FIX inhibitors detected.

“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,” Michael Parini, chief executive officer, Freeline, added to the statement.2

B-AMAZE was a multicenter, open-label, dose-finding phase trial of FLT180a. Ten adult male patients received either 3.84e11, 6.4e11, 8.32e11 or 1.28e12 vg/kg of FLT180a in the B-AMAZE trial as well as a prophylactic immune management regimen of prednisolone with or without tacrolimus. These participants had severe (FIX activity <1%) or moderately severe (FIX activity 1-2% with severe bleeding phenotype) hemophilia B. No patients had AAVS3 neutralizing antibodies before enrollment. The study primarily assessed safety as measured by the incidence and severity of AEs, and efficacy, as assessed by FIX levels at week 26. Secondary endpoints included changes in ABR and FIX consumption, development of FIX inhibitors, and clearance of viral genomes.

“Gene therapy is still a young field that pushes the boundaries of science for people with severe genetic diseases,” study author Amit Nathwani, MD, PhD, Professor of Hematology, University College London Cancer Institute, co-founder and board member, Freeline, added to the statement.2 “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.”

Freeline also recently announced updated data from the first 3 patients dosed in cohort 1 of phase 1/2 dose-confirmation B-LIEVE trial (NCT05164471) with 7.7e11 vg/kg of FLT180a.3 These patients demonstrated a rapid increase of FIX to normal levels of 93, 92 and 80 IU/dL through days 77, 56 and 36, respectively, as of the data cut-off of May 23, 2022. Patients all stopped and did not have to resume FIX prophylaxis after treatment. The second cohort completed dosing in June 2022 and the data from this cohort so far seem to support that of cohort 1. FLT180a was well-tolerated at this dose, with no serious AE.

1. Chowdary P, Shapiro S, Makris M, et al. Phase 1–2 trial of AAVS3 gene therapy in patients with hemophilia B. N Engl J Med. 2022; 387:237-247 doi: 10.1056/NEJMoa2119913
2. New England Journal of Medicine publishes positive long-term data on Freeline’s gene therapy candidate FLT180a for people with hemophilia B. News release. Freeline Therapeutics. July 21, 2022. https://finance.yahoo.com/news/england-journal-medicine-publishes-positive-110000513.html
3. Young G, Chowdary P, Barton S, Yee D, Flight P, Ferrante F. Results from B-LIEVE, a Phase 1/2 Dose-Confirmation Study of FLT180a AAV Gene Therapy in Patients with Hemophilia B. Presented at: 2022 ISTH Congress, July 9-13, London, UK.