By Erin Harris, Editor-In-Chief, Cell & Gene
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A clinical hold from the FDA can significantly prolong the time and increase the cost of drug development. Recently, the FDA lifted the clinical hold on Astellas Pharma’s FORTIS Ph1/2 trial clinical trial evaluating the safety, tolerability, and efficacy of investigational AT845 in adults with late-onset Pompe disease (LOPD). Ha Tran, Executive Medical Director at Astellas Pharma, and I caught up to discuss the cause of the clinical hold and the future of the program now that the hold has been lifted. Here’s what she had to say.
Pompe disease is a rare, severe, autosomal recessive metabolic disease characterized by progressive muscular degeneration. The overall incidence is estimated to be approximately 1 in 40,000 births, although frequency and disease progression varies with age of onset, ethnicity and geography. The disease is caused by mutations in the GAA gene that prevent the production and function of a protein called acid alpha-glucosidase (GAA). GAA is responsible for metabolizing glycogen, and dysfunction or absence of this protein results in the accumulation of glycogen in tissues, primarily in the skeletal and cardiac muscles, where it causes damage to tissue structure and function. Currently, the only approved treatment for Pompe is enzyme replacement therapy (ERT), which is a chronic treatment delivered in bi-weekly infusions and relies solely on tissue uptake of GAA from plasma. Late-onset Pompe disease (LOPD) is characterized by slowly progressive skeletal myopathy (Hirschhorn, 2001) with proximal muscle weakness and respiratory insufficiency. Nearly all patients with LOPD decline over time requiring full-time use of a wheelchair for mobility (Chien, 2013), and experience progressive respiratory decline which leads to full-time ventilator use and can lead to early death (Hagemans, 2006).
What was the cause of the clinical hold?
The FDA placed a clinical hold on the FORTIS Ph 1/ 2 trial following the occurrence of a serious adverse event (SAE) of peripheral sensory neuropathy in one of the trial participants. The SAE was classified by the site investigator as Grade 1 (mild in severity) and deemed serious due to medical significance.
How did you and your team work with FDA to reach the goal of lifting the clinical hold?
AGT submitted a Complete Response to the clinical hold on December 20, 2022, which the FDA reviewed during the last 30 days. This submission included responses to the FDA’s clinical hold questions, including a comprehensive summary overview of the SAE and summary of a root cause analysis conducted by AGT to understand the etiology of the peripheral sensory neuropathy.
Now that the hold has been lifted, what does that mean for the future of the program?
Following the clinical hold lift, Astellas is working to complete clinical and regulatory activities necessary to resume dosing and continue the FORTIS clinical trial. Until these activities are completed, we cannot comment on timing expectations.
What advice do you have for other CGT companies regarding clinical holds? What did you learn throughout this process?
During this process, we always kept patient safety as the most important focus of every piece of our work. It’s also important to ensure a thorough investigation and keep all relevant stakeholders engaged and informed. In addition, it’s crucial to keep a close communication with the patient community, health authorities and study sites.
We would also like to reiterate the importance of a potential new treatment for Pompe disease. The only approved treatment for the disease currently is enzyme replacement therapy (ERT), which is a chronic treatment delivered in bi-weekly infusions and relies solely on tissue uptake of GAA from plasma. There is still a significant unmet need for patients with Pompe due to long-term efficacy limitations of ERT and immunogenicity risks. We are grateful to the patients participating in the FORTIS clinical trial, and we remain committed to safely developing novel therapies for those with a high unmet medical need. Patients drive everything we do within Astellas Gene Therapies, and this is another step forward in finding better treatments for Pompe disease.