A Single Intravenous Infusion of FLT180a Results in Factor IX Activity Levels of More Than 40% and Has the Potential to Provide a Functional Cure for Patients with Haemophilia B

Introduction: Haemophilia B is an X-linked disease caused by mutations of the F9 gene coding for Factor IX (FIX). It is classified as mild, moderate, or severe based on FIX level, which correlates to clinical outcomes including frequency and severity of bleeding. Current standard of care is regular prophylaxis with FIX concentrate which aims to maintain FIX level above 1% to decrease the annualised bleed rate (ABR). However, compliance is variable and treatment is expensive so not available to all patients. Somatic gene therapy for haemophilia B offers the potential for durable endogenous production of FIX after a single infusion. A number of gene therapies for haemophilia B are in development and have shown the ability to raise FIX activity and reduce ABR and factor consumption. The most significant adverse effect observed to date, is a self-limiting increase in liver enzymes occurring between Week 4 and 12, which is associated with a loss of FIX expression. This can be treated with steroids but these must be started without delay to be fully effective and prevent loss of FIX expression. FLT180a is a next generation gene therapy for the treatment of haemophilia B consisting of single stranded adeno-associated virus (AAV) in which a codon optimised variant FIX transgene is under the control of a new small synthetic liver specific promoter and is encapsidated in a novel synthetic capsid that has been shown to significantly improve the transduction of human hepatocytes. Based on in-vitro and in-vivo data, FLT180a has the potential to produce continuous high levels of endogenous FIX activity sufficient to normalise FIX levels and eliminate the risk of spontaneous and traumatic bleeds, thus allowing patients to lead a normal life.

Methods: In this first-in-human Phase 1/2, open-label, multicentre, ascending single dose, safety study sponsored by UCL (NCT03369444) FLT180a is administered to patients with severe (<1% FIX activity) or moderate (1-2% FIX activity with a severe bleeding phenotype) haemophilia B, with no current/previous evidence of inhibitors and a negative transduction inhibition assay for the vector. The primary endpoint is safety. Secondary endpoints include FIX activity levels, ABR, FIX consumption, immune response, and viral shedding. To address the risk of transaminitis and protect against loss of gene expression all patients participating in the study are to receive prophylactic steroids between Week 4 and Week 12.

Results: As of 26 June 2018, two patients had been treated with FLT180a at the low dose of 4.5 x 10¹¹ vg/kg and observed for 20 and 14 weeks, respectively. Within 4 weeks of receiving a single infusion of FLT180a, both patients achieved FIX levels of >30%, which is well within the mild haemophilia range where the risk of spontaneous bleeding is absent and bleeding occurs only after major surgery or injury. Patients 1 and 2 had peak FIX expression around Week 12 with levels of 48% and 66%, respectively. After the discontinuation of prophylactic steroids FIX levels stabilised at 46% and 48%, respectively.

No serious adverse events have been reported and there has not been any significant increase in liver enzymes. Prophylaxis with exogenous coagulation factor was stopped within the first week post FLT180a administration due to sufficient rise in patients endogenous FIX. Neither patient has required exogenous coagulation factor after this first week. No spontaneous bleeds have occurred. A traumatic bleed was reported by Patient 1 (right middle finger cut) at Week 10 but did not require treatment with FIX concentrates. The patient's FIX activity at the time was 38%.

Conclusions: Current treatments have reduced life-threatening bleeds, chronic joint disease and disability; however, people with haemophilia B continue to have significantly decreased quality of life. This study has shown a single infusion of low dose FLT180a leads to FIX levels of >40%, greatly reducing the risk of spontaneous or traumatic bleeds and raises the prospect of achieving a functional cure by normalising FIX levels with a higher dose. This will reduce the risk of life-threatening bleeds following trauma and surgery, transform quality of life and thus represents a major therapeutic advance for people with haemophilia B.