Freeline Therapeutics Holdings plc announced new data from its ongoing Phase 1/2 MARVEL-1 dose-finding clinical trial of FLT190 for the treatment of Fabry disease and provided updates on its pipeline programs. The Company reported an interim program update on Patients One and Two and progress in its Phase 1/2 MARVEL-1 dose-finding trial of FLT190. The data cutoff date was October?6, 2021. Patient Two: Patient Two was dosed at the lowest dose cohort of 7.5e11 vg/kg in June 2021 and experienced a sustained and durable response with an increase in expression of plasma a-galactosidase A (a-Gal A), the missing enzyme in Fabry disease, to near normal levels, from 0.0 nmol/hr/mL at baseline to an average of 3.9 nmol/hr/mL from weeks 6 to 16 post-dosing. Thus far, the patient remains off enzyme replacement therapy (ERT). With respect to safety, the treatment was well-tolerated with no dose-limiting toxicities or serious adverse events (SAEs). As of the cutoff date, there were no adverse events higher than Grade 1 (mild). Patient Two has a history of cardiac disease and on routine weekly monitoring, an incidental finding of changes in cardiac markers, troponin-T and electrocardiogram (ECG), was observed, although the patient was asymptomatic. After evaluation, these findings were determined to be consistent with mild and transient myocarditis. Patient 2?s troponin-T has since reverted to baseline, and the ECG remained stable as of the cutoff date. Ventricular functioning in the heart has remained normal throughout. Patient Two has experienced no elevations in liver enzymes under current immune management regimen, which has evolved in response to patient data in the hemophilia B and Fabry programs. The total vector genome (vg) dose Patient Two received was approximately 40% higher than Patient One due to differences in their weights. Patient Two saw a 400% increase in enzyme levels compared with Patient One. Patient One: Long-term follow-up from Patient One shows durable response with plasma a-Gal A activity levels remaining elevated at two years post-dose and generally steady at an average of three times baseline. The patient had a subtherapeutic response with plasma a-Gal A at 0.8-1.3 nmol/hr/mL and restarted ERT at week six. Patient One has experienced no enduring clinical sequelae of the transient mild myocarditis episode previously reported in 2019. Ventricular functioning in the heart remained normal throughout with cardiac magnetic resonance imaging (MRI) showing no evidence of scarring on follow-up at one- and two-years post-dosing. An independent Data Monitoring Committee (DMC) conducted a comprehensive review of safety and efficacy data from the two patients dosed in the lowest dose cohort in the MARVEL-1 trial. The DMC has recommended that Freeline proceed with dosing a third patient in the first cohort at the same 7.5e11 vg/kg dose level with additional cardiac monitoring, which will be followed by an additional DMC meeting. The Company is engaging with regulatory authorities to update the study protocols and trial design for FLT190 and expects to continue patient dosing in the first quarter of 2022 following these updates. Freeline continues to anticipate interim data readouts from the MARVEL-1 trial in 2022, sharing further efficacy and safety data. Hemophilia B: On track to report long-term durability data from the Company?s Phase?1/2 dose-finding trial of FLT180a for the treatment of hemophilia?B by year-end. The Company is engaging with regulatory authorities to update the study protocol for the Phase?1/2 B-LIEVE dose-confirmation trial of FLT180a. The protocol changes and subsequent review shifts guidance by approximately one quarter for the FLT180a program, with study start expected in the first quarter of 2022 instead of by year-end 2021. The company is currently evaluating the timing of Phase 3 pivotal trial and filing of a Biologics License Application and will provide more concrete guidance next year. The Company continues to anticipate interim data readouts in 2022. Pursuing Accelerated Approval with the U.S. Food and Drug Administration (FDA) using the surrogate endpoint of factor IX (FIX) activity levels combined with demonstration of a positive correlation between 26-week FIX activity levels and 52-week annualized bleeding rate (ABR), assuming robust data at 26 weeks. Enrollment in the ECLIPSE run-in study for the Phase 1/2 B-LIEVE dose-confirmation trial of FLT180a is proceeding more quickly than expected. As a result, the company believes it identified a sufficient number of patients to fully enroll the B-LIEVE trial. Gaucher Disease Type 1: Announced Orphan Drug Designations for FLT201 for the treatment of Gaucher disease Type 1 from the FDA and European Commission (EC). The Company is engaging with regulatory authorities to update the study protocol for the Phase?1/2 dose-finding trial of FLT201 and remains on track for trial site initiation by year end 2021. The company continue to expect trial start and interim data readouts on safety and efficacy in 2022. Hemophilia A: The Company expects to complete ongoing preclinical studies of FLT210 for the treatment of hemophilia A by year end as previously anticipated. Based on data generated in these studies to date, the Company is evaluating whether additional studies will enhance an IND filing and the necessity of conducting these additional studies. Platform Technology: The Company presented two preclinical posters at the 2021 European Society for Gene and Cell Therapy Virtual Congress detailing analysis methods for liver transduction and expression in non-human primate liver after AAVS3 delivery and the Company?s second generation two-plasmid packaging system for AAV vectors to improve quality and yield.