Freeline publishes further data for FLT180a

Syncona Ltd, a leading healthcare company focused on founding, building and funding a portfolio of global leaders in life science, announces that its portfolio company, Freeline, is presenting further data from the ongoing B-AMAZE Phase 1/2 clinical trial investigating a novel gene therapy, FLT180a for Haemophilia B, at The European Association for Haemophilia and Allied Disorders (EAHAD) conference.

The presentation is entitled: “Phase 1/2 preliminary data from B-AMAZE study of adeno associated virus (AAV) gene therapy (FLT180a) confirms progress towards achieving Factor IX levels in the normal range for patients with severe or moderately severe Haemophilia B.”

Chris Hollowood, Chief Investment Officer of Syncona and Executive Chairman of Freeline, said: “We are highly encouraged by the data being generated in our lead programme in Haemophilia B. We believe that Freeline has developed a product that could be best-in-class for patients living with Haemophilia B. A functional cure was an aspiration of Freeline’s when the business was founded just under five years ago and this data takes an important step towards that goal. We look forward to identifying the optimal dose in the coming months and subsequently moving the product into a pivotal trial.

The data also demonstrates the power of our next generation capsid. The step change in performance delivered by the capsid will allow Freeline to lead the systemic gene therapy space beyond Haemophilia to diseases, such as Fabry Disease and Gaucher Disease, where high expression levels will be needed for meaningful clinical impact.”

Trial background

Freeline is a systemic gene therapy company focused on liver expression of proteins for a range of chronic diseases. Freeline uses a novel capsid which is capable of driving high protein expression. FLT180a is a next-generation AAV gene therapy for people with Haemophilia B that leverages this next-generation capsid. Freeline is seeking to identify the optimal dosing regimen for FLT180a with the goal of delivering to patients Factor IX (FIX) activity levels between 70 to 150 per cent, in the upper part of the normal range, which no other treatment has been able to achieve to date.

The normal range of FIX activity in the general population's blood is between 50 per cent and 150 per cent and patients diagnosed with severe and moderate Haemophilia B have FIX activity below five per cent.

Update on data

Reportable data^[1] is available for eight patients who have been treated across four dose cohorts with FLT180a. The first dose cohort (two patients) has follow-up over 78 weeks, the next two dose cohorts (two patients in each) have data available over 26 weeks and the most recent dose cohort (two patients) have FIX activity level readings available after three weeks:

• Dose Level One: Two patients treated with the lowest dose, 4.5x10¹¹ vector genomes/kg body weight and had average FIX level activity at 78 weeks of 43.5%
• Dose Level Two: Two patients received a single dose at 1.5x10¹² vector genomes/kg body weight and had average FIX level activity at 26 weeks of 160%

• One patient within the cohort experienced a rise in ALT (see below) that was followed by a decline in expression at 26 weeks

• Dose Level Three: Two patients received a single dose at 7.5x10¹¹ vector genomes/kg body weight and had average FIX activity at 26 weeks of 32%

• One patient within the cohort experienced a rise in ALT that was followed by a decline in expression at 26 weeks

• Dose Level Four: Two patients received a single dose at 9.75x10¹¹ vector genomes/kg body weight and had average FIX activity at three weeks of 109%

All patients had severe or moderate Haemophilia B with baseline FIX activity levels prior to gene therapy of 2 per cent or less.

In the low dose cohort, stable expression of FIX activity has now been seen for over 18 months. Six patients have completed follow-up for six months, and amongst those, three have FIX activity levels over 50%. The two patients in dose level four (9.75x10¹¹) have shown encouraging early expression and the current focus is to expand this dose cohort to establish safety and efficacy.

No patients in the trial have had any bleeding episodes requiring treatment or required any FIX supplementation post gene therapy.

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. Systemic gene therapy programmes often show rises in ALTs between months one and six. Freeline has been developing its immunosuppression regimen throughout the trial, to seek to identify a regimen that consistently controls ALTs and therefore provides patients receiving therapy with the maximum confidence of normal activity. The business continues to evolve this and has implemented a regimen for dose level four involving prophylactic corticosteroids and tacrolimus^[2]. Immunosuppression appears to be effective in controlling ALTs and there were no clinical symptoms associated with ALT rises. No ALT rises were observed in the low dose cohort (4.5x10¹¹).

Further data is in the table below.

Next steps

Freeline continues to enrol Haemophilia B patients as part of its Phase 1/2 dose-ranging trial in order to identify the optimal dose to achieve normal FIX activity levels and will provide a further update in H2 CY2020.

Valuation

In line with Syncona's valuation policy, we continue to hold our investment in Freeline at fair value based on cost until material clinical data is generated, or a third-party financing or other factor occurs, that indicates that cost is no longer the appropriate measure of fair value. Syncona anticipates that the point at which Freeline selects the optimal dosing regimen for FLT180a and indicates that it will move to a pivotal trial, it will constitute material clinical data.

Syncona remains the sole institutional investor in Freeline alongside UCL Technology Fund. Syncona has a 79 per cent fully diluted stake in Freeline which as at 31 December 2019 is valued at £148.6 million.

Data table

*Patients received steroids after week 3 

**One patient within this cohort experienced a rise in ALT that led to a decline in expression at 26 weeks

¹ As at cut-off date of 24 January 2020

² An immunosuppressive drug widely used in transplantation surgery.

³ Local FIX activity assay data

[3] Local FIX activity assay data

[1] As at cut-off date of 24 January 2020

[2] An immunosuppressive drug widely used in transplantation surgery.