Freeline, a clinical stage, Adeno-Associated Virus (AAV) based gene therapy company with the ambition of transforming the lives of patients suffering from inherited systemic debilitating diseases, today announced new data on its AAV gene therapy product candidate, FLT180a, in severe Haemophilia B patients at the International Society on Thrombosis and Haemostasis (ISTH) 2020 Congress. The data presented in an oral presentation by Professor Pratima Chowdary of the Katharine Dormandy Haemophilia and Thrombosis Centre, Royal Free Hospital UK and UCL Cancer Institute, and Principal Investigator for the study, demonstrated with data up to two years for the earliest cohort, that a dose of between 7.5e11 and 9.75e11 vg/kg has the potential to create durable Factor IX (FIX) activity levels in the normal range in patients with severe Haemophilia B.
"We are delighted to report additional data from the first 10 patients treated in our Haemophilia B trial,” said Theresa Heggie, CEO of Freeline. “These data build on previously reported data which suggest that FLT180a has the potential, using relatively low doses, to create durable FIX activity levels in the normal range in patients with severe Haemophilia B and provide a functional cure.”
“The clinical data shows the progress we have made in achieving Factor IX levels in the normal range for people with severe or moderately severe Haemophilia B, which has the potential to markedly improve their quality of life,” added Professor Pratima Chowdary of the Katharine Dormandy Haemophilia and Thrombosis Centre, Royal Free Hospital, and UCL Cancer Institute, UK .
Reportable data[1] is available for 10 patients who have been treated with FLT180a across 4 dose cohorts. All patients had severe or moderate Haemophilia B with baseline FIX activity levels prior to gene therapy of 2% or less. The first dose cohort (2 patients) has follow-up over 104 weeks, the next 2 dose cohorts (2 patients in each) have data available over 26 and 52 weeks, respectively. The most recent dose cohort (4 patients) has FIX activity level readings available at 3 weeks, with 2 of those patients also having data available at 26 weeks.
Long term durability up to 2 years was seen in the 2 patients in the lowest dose cohort (4.5e11 vg/kg) with an average FIX level activity at 52 and 104 weeks, both of 38%, which are levels commonly associated with mild Haemophilia B. There was no evidence of transaminitis and transient steroid induced increases in FIX activity levels were observed in both patients.
Durable FIX activity levels in the normal range were seen at doses of 7.5e11 and 9.75e11 vg/kg. Two patients received a dose of 7.5e11 vg/kg and at 3 weeks each had comparable expression at 25.5% (26% and 25%). At week 26, one of the 2 patients experienced a rise in alanine aminotransferase (ALT)[2] that was followed by a decline in expression. The other patient went on to have a normal FIX activity level of 60% at week 52. In addition, 4 patients received a dose of 9.75e11 vg/kg and at week 3 their respective FIX activity levels were 136%, 82%, 73% and 105%. Two patients from this dose cohort have now reached 26 weeks post-infusion and have shown FIX activity levels of 139% and 57%; the latter case in a patient who experienced an increase in ALT which resulted in a reduction in FIX expression. Two patients received a higher dose of 1.5e12 vg/kg. This was deemed by the Company to be a higher dose than required for the potential treatment of Haemophilia B. Average FIX expression at 26 weeks was 160%, including 1 patient with reduction in FIX expression following transaminitis. To date no bleeds have required supplemental FIX in any of our patients studied.
Freeline has continued to optimise its prophylactic immune management regimen throughout the trial, with an aim both to consistently control ALT levels to prevent loss of FIX expression. The current immune management regime, using prophylactic corticosteroids and tacrolimus[3], was implemented for the last three patients in the 9.75e11 vg/kg dose level.
Freeline also presented data on the FIX Padua variant and health economics from its AAV-based Haemophilia gene therapy platform in five poster presentations at the conference.
Title: Multi-centre field study of one-stage and chromogenic Factor IX assays in samples containing the Factor IX Padua variant
Abstract No: A-1120-0035-00542
Freeline presented the outcome of a multicentre field study performed to evaluate the performance and intra- and inter-lab variability of one-stage and chromogenic FIX assays in measuring FIX-Padua activity. Freeline’s FIX-Padua field study shows that routinely used FIX assays can yield differences in FIX activity levels which vary over 3-fold while controls showed relatively little variation.
Title: Mechanistic evaluation of Factor IX-Padua activity in chromogenic FIX and thrombin generation assays
Abstract No: A-1120-0035-00721
Freeline’s trial featuring its AAVS3 FIX-Padua product candidate, known as FLT180a, is targeting FIX-Padua expression levels that functionally cure Haemophilia B. Recent data shows that FIX-Padua activity (FIXp:C) assay results can vary by up to 3-fold depending on the assay used. Interpretation of gene therapy clinical outcomes may be difficult where there is up to a 3-fold variation in FIX:C range, emphasising the need to understand mechanisms causing FIX assay discrepancy and how Padua FIX (FIXp:C) functionally compares to wild-type FIX (FIXwt:C). A thorough understanding of FIXp:C assays will more accurately identify the appropriate expression target in clinical trials and inform on which assays are most suitable for monitoring gene therapy patients. The data suggests that one-stage FIX assays may provide a better estimate of FIXp:C and this activity is similar to FIXwt:C in driving physiologically relevant thrombin generation.
Title: Feasibility of Using Hospital Episode Statistics in England to Assess the Resource Use and Outcomes in Haemophilia
Abstract No: A-1120-0033-02562
Title: The Relationship between Societal Costs Associated with Haemophilia and Disease Severity: A Regression Analysis Using CHESS II Data
Abstract No: A-1120-0033-02935
Title: Modelling the Cost of Equivalent trough Level across Gene Therapy and Factor IX Replacement Therapy in Haemophilia B
Abstract No: A-1120-0033-02961
In these 3 posters, Freeline highlighted the potential economic and societal importance of gene therapy treatment for Haemophilia B which results in FIX activity in the normal range. The current standard of care in Haemophilia B is regular infusions with factor replacement therapy, with novel treatments, including Freeline’s Haemophilia B gene therapy candidate, seeking to minimise the administration burden of treatment while providing greater protection against bleeding episodes and joint damage.
Additional data were presented which models the cost of FIX replacement therapy required to achieve different trough levels equivalent to three hypothetical steady-state expression levels of a gene therapy. In addition, Freeline presented an analysis of the societal costs for patients in the mild range of Haemophilia from the CHESS II dataset, which suggests that higher levels of factor within the mild range (20-40%) incur lower per patient costs than patients at the lower end of the mild range (5-20%), even accounting for age, BMI and country effects. Freeline also discussed the feasibility of utilising NHS England’s hospital episode statistics (HES) to assess resource use and clinical outcomes in the secondary healthcare setting for Haemophilia.
[1] As at cut-off date of 15 June 2020
[2] Alanine aminotransferase (ALT) is an enzyme that is predominantly found in the liver. Damage to liver cells can lead to release of more ALT in the bloodstream and therefore ALT levels in the blood can be used as a marker of liver damage or toxicity, and risk of loss of FIX expression.
[3] An immunosuppressive drug widely used in transplantation surgery.