Fabry Disease Gene Therapy Shows Efficacy in First 2 Patients


The first patient with Fabry disease dosed with FLT190 2 years ago continues to have elevated, sustained α-Gal A.

FLT190, Freeline Therapeutics’ investigative gene therapy for the treatment of Fabry disease, has so far shown efficacy in the 2 patients dosed in the phase 1/2 MARVEL1 study (NCT04040049).

“Enzyme expression data from the second patient in our phase 1/2 dose-finding trial of FLT190 are highly encouraging, with expression of alpha-galactosidase A reaching near-normal levels and the patient thus far remaining off enzyme replacement therapy since dosing,” Michael Parini, chief executive officer, Freeline, said in a statement. “These results were achieved in our lowest dose cohort and already FLT190 appears to be having a significant impact on α-Gal A activity and disease process in Fabry, which is the underlying goal and promise of the FLT190 program."

The second patient in the MARVEL1 study was dosed in June 2021 in the lower dose cohort with a dose of 7.5e11 vg/kg. This patient has experienced a sustained and durable increase in plasma α-galactosidase A (α-Gal A) expression 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 after treatment as of the data cutoff date of October 6, 2021. The patient has remained off enzyme replacement therapy (ERT).

The first patient, dosed 2 years ago, has exhibited expression of plasma α-Gal A activity levels which remain generally steady at an average of 3 times the baseline value. This patient had a subtherapeutic response (plasma α-Gal A expression, 0.8-1.3 nmol/hr/mL) at 6 weeks post-treatment and restarted ERT.

READ MORE: Fabry Gene Therapy Program Discontinued Following Transient Engraftment Issues

“We will be dosing a third patient in the first dose cohort of MARVEL-1, which will allow us to gather additional information on a potential risk of mild and transient myocarditis in this patient population with underlying and contributory cardiac disease. This step is consistent with the recommendation of our independent Data Monitoring Committee (DMC), with whom we have worked to review the data,” Parini added.

In terms of safety, no dose-limiting toxicities, serious adverse events (AEs), or liver enzyme elevations were observed. An asymptomatic change in troponin-T and electrocardiogram (ECG) was observed in the second patient, who has a history of cardiac disease, and these findings were recorded as mild and transient myocarditis. Markers have since returned to and remain at baseline levels.

The first patient dosed experienced a transient mild myocarditis episode in 2019, but no enduring clinical sequelae, abnormal ventricular functioning, or scarring has been observed at follow-up at 1- and 2-years post-dosing. The second patient received around a 40% higher total vg dose than the first due to weight differences and also had a 400% increase in enzyme levels compared with the first patient.

“The mild and transient myocarditis was an unexpected observation in the MARVEL-1 study given the very strong safety record Freeline has established in hemophilia, where myocarditis was not observed in the 10 patients treated in the B-AMAZE study,” Atul B. Mehta, MB BChir, emeritus professor of hematology, University College London, and former clinical director, Lysosomal Storage Disorders Unit, Royal Free London NHS Foundation Trust, added to the statement. “It’s likely that Fabry patients are predisposed to developing this by virtue of the pre-existing cardiomyopathy they often have as a result of the disease. Appropriate measures for even closer observation and monitoring have been introduced to ensure the safety of future trial participants.”

Freeline is working to update study protocols and trial design for MARVEL1 and expects to continue patient dosing in the first quarter of 2022, with interim data readouts later in the year. The company also reported updates on their other programs in hemophilia A and B and Gaucher disease type 1.

“As Freeline and others continue to explore the potential of gene therapy, we are working with regulatory authorities to update study protocols for FLT180a for hemophilia B and FLT201 for Gaucher disease Type 1 to include additional data collection. We believe this proactive step is the right approach for patients. As a result of these updates, we expect to initiate the trial of FLT180a in the first quarter of 2022 instead of by the end of this year and continue to anticipate interim data readouts in 2022 from both trials. We also are working with regulatory authorities to augment data monitoring for FLT190 and expect to continue patient dosing in the first quarter of 2022 following these updates,” Parini added to the statement.

Freeline reports new data from Fabry disease program, pipeline and company updates, including appointment of Pamela Foulds, MD as chief medical officer, and third quarter 2021 financial results. News release. Freeline Therapeutics. November 9, 2021. https://www.globenewswire.com/news-release/2021/11/09/2330851/0/en/Freeline-Reports-New-Data-from-Fabry-Disease-Program-Pipeline-and-Company-Updates-Including-Appointment-of-Pamela-Foulds-MD-as-Chief-Medical-Officer-and-Third-Quarter-2021-Financia.html
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