Gene Therapy Well-Tolerated in Late-Onset Pompe Disease


Interim safety data from the FORTIS study were presented at WORLDSympsoium.

This content originally appeared on our sister site, NeurologyLive.

The gene therapy AT845 (Astellas Pharma) has been well-tolerated in adult patients with late-onset Pompe disease (LOPD), according to positive interim safety data from the phase 1/2 FORTIS study (NCT04174105) presented at the 18th Annual WORLDSymposium, February 7-11, 2022, San Diego, CA.1

FORTIS is an ongoing, multicenter, open-label, ascending dose trial assessing AT845, an investigational adeno-associated gene replacement therapy designed to deliver a functional GAA gene to express acid alpha glucosidase (GAA) directly into muscle cells. It is the first-in-human trial of the treatment.

The trial has enrolled 4 patients as of the December 3, 2021, cutoff date. Up to 24 weeks of follow-up data were reported for 2 patients in Cohort 1, who were dosed at 3 x 1013 vg/kg, and preliminary data was reported for 2 patients in Cohort 2, who were dosed at 6 x 1013 vg/kg. Reported safety data includes safety and tolerability assessments indicating that the treatment was well-tolerated in all participants.

“We are pleased that AT845 has been well-tolerated so far in the four adults with LOPD who have received treatment,” Weston Miller, MD, Senior Medical Director, Clinical Development, Astellas Gene Therapies, said in a statement.1 “In the 2 participants in Cohort 1 with follow-up duration through week 24 after dosing, AT845 demonstrated an encouraging safety profile.”

WATCH NOW: Importance of Screening and Early Treatment in Genetic Disorders: Paul Wuh-Liang Hwu, MD, PhD

Miller stated that, notably, there were no serious adverse events reported in any of the 4 participants thus far, adding, “One participant experienced elevated transaminases, which is considered a common immune-mediated treatment response based on the time of onset after dosing, its presentation during steroid taper initiation and its reversal with steroid re-initiation. These safety data are encouraging, and the program continues to enroll participants.”

Primary end points for the study included safety and efficacy of AT845 in this patient population, as well as efficacy, with investigators looking to observe change in muscle GAA protein expression and enzyme activity from baseline. Improvements in respiratory, endurance, and quality of life measures comprise the secondary end points. Participants in the FORTIS study receive a 1-time peripheral intravenous (IV) infusion of AT845, which is followed by 1 year of monitoring for safety, clinical, and biochemical end points. This includes GAA activity and protein level in patients’ muscles, as well as 4 additional years of long-term safety monitoring.


The only approved therapy for treatment of Pompe disease is enzyme replacement therapy (ERT). In August 2021, Sanofi announced that the FDA granted approval to avalglucosidase alfa-ngpt (Nexviazyme) for the treatment of LOPD in patients aged 1 year and older. The biologics license application for the long-term ERT was  originally accepted for review in late 2020, after receiving breakthrough therapy and fast track designations. This treatment approach relies solely on tissue uptake of GAA from plasma and is delivered via biweekly IV infusions, with a recommended dose based on body weight—20 mg/kg for patients weighing 30 kg or heavier, and 40 mg/kg for those patients under 30 kg—and is administered incrementally via IV infusion.2,3

“There is significant unmet need for patients with Pompe disease due to the short half-life, inefficient uptake in the key tissues affected by the disease and the immunogenicity of ERT,” Tahseen Mozaffar, MD, professor of neurology, pathology, and orthapaedic surgery; and director, Division of Neuromuscular Diseases, Neurology School of Medicne, UC Irvine, said in a statement.1 “AT845 has the potential to be a best-in-class approach as a muscle-directed gene therapy using an AAV8 capsid serotype. It is being investigated to determine whether it can deliver a functional GAA gene that is efficiently transduced to express GAA directly in tissues affected by the disease, including skeletal and cardiac muscle.”

1. Astellas announces positive safety data from the FORTIS study of AT845 in adults with late-onset Pompe disease. News release. February 7, 2022. Accessed February 8, 2022.
2. FDA approves Nexviazyme® (avalglucosidase alfa-ngpt), an important new treatment option for late-onset Pompe disease. News release. Sanofi Genzyme. August 6, 2021. Accessed February 8, 2022.
3. FDA grants priority review for avalglucosidase alfa, a potential new therapy for Pompe disease. News release. Sanofi. November 18, 2020. Accessed February 8, 2022.
Related Videos
Paul Harmatz, MD
Mitchel Horwitz, MD
Bruce Cree, MD, PhD, MAS, a professor of neurology and the clinical research director of the University of California San Francisco (UCSF) Multiple Sclerosis Center
Paul Harmatz, MD
Emilie Aschenbrenner, PharmD, BCOP, a hematology coordinator for pharmacy at Froedtert and the Medical College of Wisconsin
Nirav N. Shah, MD
Alexis Kuhn, PharmD, BCOP, a pediatric oncology pharmacist at the Mayo Clinic
Haydar Frangoul, MD
Aimee C. Talleur, MD, a physician at St. Jude Children’s Research Hospital
© 2024 MJH Life Sciences

All rights reserved.