AT845 Shows Promising Efficacy for Late-Onset Pompe Disease in Phase 1/2 Trial


Three of 4 patients withdrew from their previous enzyme replacement therapy following treatment with AT845 gene therapy.

Jordi Díaz-Manera, MD, PhD, professor of neuromuscular disorders and Honorary Consultant Clinical Geneticist for the Newcastle Hospitals NHS Foundation Trust at Newcastle University, United Kingdom

Jordi Díaz-Manera, MD, PhD

This content originally appeared on our sister site, CGTLIVE.

Recent interim data from the phase 1/2 FORTIS clinical trial (NCT04174105) assessing Astellas Pharma’s AT845 displayed promising efficacy for the treatment of late-onset Pompe disease (LOPD).1,2 AT845, an investigational adeno-associated virus (AAV) vector-based gene replacement therapy, is intended to deliver a functional copy of the acid alpha-glucosidase (GAA) gene with a muscle-specific promotor via an AAV8 vector with tropism to muscle tissue.

Among the 4 patients treated with AT845 in the FORTIS trial so far, 3 have ceased treatment with their prior standard of care treatment, enzyme replacement therapy (ERT). Patient 1, a 52-year-old male patient with 68 weeks of follow-up, withdrew from ERT at 17 weeks post-treatment with AT845; Patient 3, a 66-year-old male patient with 54 weeks of follow-up, withdrew from ERT at 10 weeks post-treatment; and Patient 9, a 49-year-old female patient with 43 weeks of follow-up, withdrew from ERT at 24 weeks. Patient 2, a 48-year-old female patient with 78 weeks of follow-up, has not withdrawn from ERT. Patient 2 and Patient 1 received a dose of 3.0x1013 vg/kg of AT845 and Patient 3 and Patient 9 received a dose of 6.0x1013 vg/kg of AT845.

The findings were presented as an abstract by lead author Jordi Díaz-Manera, MD, PhD, professor of neuromuscular disorders and Honorary Consultant Clinical Geneticist for the Newcastle Hospitals NHS Foundation Trust at Newcastle University, United Kingdom, and colleagues at the WORLDSymposium 2023, held February 22-26, in Orlando, Florida.

"There is tremendous need for new treatment approaches in progressive, debilitating, genetic diseases like LOPD that move beyond standard of care enzyme replacement therapy (ERT)," Díaz-Manera said in a statement.1 "AAV gene therapies have the potential to be a safe and effective approach to delivering a functional GAA gene directly to the muscle tissues in patients with LOPD."

All patients showed stable forced vital capacity over time post treatment of AT845, including after ERT withdrawal. Similarly, patients’ performance on the 6-Minute Walk Test remained stable over time following treatment, including after ERT withdrawal. On the Patient-Reported Outcomes Measurement Information System (PROMIS) Item Bank v1.0 Fatigue-Short Form 8a, Patients 2, 1, and 3 expereinced stable scores after treatment, while Patient 9’s score trended towards improvement from baseline. In addition, on PROMIS scales for ability to participate in social roles and activities, sleep disturbance, and physical function, the 4 patients also displayed stability over time. Notably, patients also had stability on measures of ability to perform daily activities and social participation on the Rasch-built Pompe-specific Activity instrument scale following treatment with AT845.

As for safety, most treatment-emergent adverse events (AEs) were grade 1 and deemed unrelated to AT845. One participant experienced an infusion-related reaction which was resolved with oral diphenhydramine and acetaminophen. Furthermore, 3 of the 4 patients showed cases of transaminitis during their steroid taper which were deemed related or possibly related to AT845. All cases were resolved with modifications to the steroid taper.

Anti-GAA antibodies were not detectable in 3 of the patients prior to treatment with AT845; at approximately 1 year following infusion, these patients continue to have no detectable anti-GAA antibodies. Patient 1 showed varying levels of anti-GAA antibodies since the initial screening; however, at 1 year of follow-up, there was no increase observed in anti-GAA antibodies from the time of infusion.

“We are excited to share these new findings from the ongoing FORTIS clinical study of AT845,” Ha Tran, executive medical director, Astellas Pharma, said in a statement.2 “These data, along with our recent announcement of the clinical hold lift of the FORTIS clinical trial, are very positive developments for the program. The preliminary data presented are encouraging. We look forward to continuing the FORTIS clinical trial as we advance towards our goal of developing innovative gene therapies and bringing new potential treatments to patients with high unmet need.”

In January 2023, the FDA lifted a clinical hold on the trial, which is the first-in-human trial of the gene replacement therapy, which is designed to use the adeno-associated virus vector 8 to deliver a functional copy of the GAA gene under a muscle-specific promoter.3 The trial was formerly was placed on hold because of a case of a serious adverse event (AE) of peripheral sensory neuropathy.4 The AE was classified as grade 1 and mild although it was serious because of medical significance. Therefore, the FDA told Astellas that there was not enough information for assessing the risks of the participants and that more information is needed about the incidence of neuropathy.

Previously, positive interim safety data from FORTIS on 4 participants were presented by Astellas Pharma at the 18th Annual WORLDSymposium, February 7-11, 2022.5 The follow-up data observed 2 patients dosed at 3 x 1013 vg/kg in Cohort 1, and preliminary data with 2 patients dosed at 6 x 1013 vg/kg in Cohort 2. All told, the therapy was well-tolerated with a positive safety profile, and no serious AEs observed.

The trial is a multi-center, dose-ascending, open-label study that primarily evaluates the therapy for safety in participants with LOPD. Participants receive a 1-time peripheral intravenous (IV) infusion of AT845 and are followed for 1 year for safety, clinical, and biochemical endpoints and then for 4 years for long-term safety monitoring. Follow-ups will assess GAA activity and protein level in patients’ muscles, as well as efficacy, measured by change in muscle GAA protein expression, and enzyme activity. Secondary endpoints include improvements in respiratory, endurance, and quality of life measures.

Currently, the only approved therapy for Pompe disease is enzyme replacement therapy (ERT). In August 2021, the FDA granted approval for Sanofi's avalglucosidase alfa-ngpt (Nexviazyme) for patients aged 1 year and older with LOPD. In late 2020, the biologics license application for the long-term ERT was originally accepted for review  after receiving breakthrough therapy and fast track designations. This therapy method depends solely on tissue uptake of GAA from plasma and delivered via biweekly with IV infusions, based on the recommended dose according to body weight—20 mg/kg for patients weighing 30 kg or heavier, and 40 mg/kg for those patients under 30 kg—and administered in increments via IV infusion.6,7

1. Diaz-Manera J, Mozaffar T, Longo N, et al. AT845 gene replacement therapy for late onset Pompe disease: An update on safety and preliminary efficacy data from FORTIS, a phase I/II open-label clinical study. Presented at WORLDSymposium 2023, held February 22-26, in Orlando, Florida. Abstract #95
2. Astellas announces update on preliminary safety and efficacy data from FORTIS study of investigational AT845 in adults with late-onset Pompe disease. News release. Astellas Pharma Inc. February 22, 2023. Accessed February 24, 2023.
3. Astellas Announces Hold Lifted by FDA on FORTIS Clinical Trial of AT845 Investigational Treatment for Adult Patients with Late-Onset Pompe Disease. News release. Astellas Pharma. January 20, 2023.
4. 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.
5. 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.
6. 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.
7. FDA grants priority review for avalglucosidase alfa, a potential new therapy for Pompe disease. News release. Sanofi. November 18, 2020. Accessed February 8, 2022.
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