PompeDiseaseNews and the AMDA have just reported that Audentes Therapeutics has begun recruiting Late Onset Pompe Disease (LOPD) patients for a new Phase 1/2 Gene Therapy clinical trial that utilizes the AAV8 vector to deliver a functional copy of the human GAA gene.

This is, of course, very exciting news. In my research, I’ve only found two Gene Therapy clinical trials for Pompe Disease – the initial University of Florida study (2010-2015) and the current Duke University clinical trial of ACTUS-101. In contrast to the on-going Duke study, this therapy delivers a functional copy of the GAA gene directly to the nucleus of muscle cells instead of utilizing the liver to express GAA. Audentes Therapeutics anticipates that this method may be more effective in targeting muscle tissues as it bypasses entirely the use of plasma to transport GAA from the liver to muscles tissues.

The trial goal is to recruit eight LOPD patients between the ages of 18 and 80. Subjects will receive a single IV dose of AT845. Two dose levels are intended to be tested – the second cohort may receive a higher dose if the initial lower dose level is found to be safe. Patients will be evaluated for primary and secondary outcomes at 48 weeks and then followed for five years.

As with most all clinical trials, there are numerous inclusion and exclusion criteria. Trial sites include three US locations (Stanford, UC-Irvine and the University of Utah), one in the UK (Newcastle Upon Tyne Hospitals Foundation Trust Clinical Research Facility) and one in Germany (Ludwig-Maximillians University of Munich). The trial began recruiting today (8/5/2020) with a primary completion date anticipated to occur by December 2022. The overall study is expected to conclude around January 2027.

From the company’s announcement:

Q: How does Audentes’ investigational gene therapy product work?

A: This investigational gene therapy product is comprised of a working copy of the GAA gene, and the new gene is placed inside a vector, which acts as a transportation vehicle and carries the gene to the appropriate cells in the body. A virus is selected as a vector because of its ability to enter the body’s cells. In this case, a very small and simple virus called adeno-associated virus (AAV) is used because it is not known to cause viral illness in people. The vector is administered one time through an intravenous injection and carries the new gene to the control center of the cells, also known as the nucleus. Once inside the muscle cell nucleus, the new gene tells the body’s cells how to make the protein, or GAA, it needs.

Q: How does Audentes’ investigational gene therapy approach differ from other approved treatments and investigational gene therapies?
A: The goal of Audentes’ investigational gene therapy approach is to express GAA preferentially in muscle tissues, including skeletal and cardiac muscle, which are the tissues most affected by the disease.

This approach differs from approved enzyme replacement therapy (ERT) and liver-directed investigational gene therapy candidates that must overcome the challenges of GAA uptake into muscle from plasma, a liquid that makes up about half of the content of blood. The main role of plasma is to take nutrients, hormones, and proteins to the parts of the body that need it. In the case of liver-directed gene therapy products, plasma transports GAA from the liver to the muscle tissue. The ERT and liver-directed approaches leverage a delivery system that may impact the amount and distribution of GAA in the muscle tissue.

Q: What are the objectives of FORTIS?
A: The objectives of the clinical trial are to evaluate the following:

The safety of 2 dose levels of the investigational gene therapy product in trial participants 18 years of age or older with LOPD

Acid alpha-glucosidase (GAA) activity and preliminary efficacy of 2 dose levels of the investigational gene therapy product in participants 18 years of age with LOPD

Q: How many people will take part in this investigative clinical trial?
A: Up to approximately 8 people are expected to be in this trial in North America and Europe. Patients who meet eligibility are not guaranteed enrollment into the trial.For specific clinical trial site information, please visit www.clinicaltrials.gov and enter “Pompe” in the “condition or disease” section and “FORTIS” in the “other terms” section. Click on “Gene Transfer Study in Patients with Late Onset Pompe Disease.”

• Interview with Dwight Koeberl, MD, PhD at Duke University
• Early results from Actus-101 phase 1/2 study (AAV2/8-LSPhGAA in Late-Onset Pompe Disease)
• First three people enrolled
• Have participated in 24 weeks of the study
• Results from low-dose branch
• No serious adverse events
• All three patients met efficacy goals and have now stopped ERT infusions entirely
• Clinical Trial Website
  • https://clinicaltrials.gov/ct2/show/NCT03533673
• Asklepios BioPharmaceutical
  • http://www.askbio.com

My Take:

This is really great news. The results are very preliminary, but the fact that all three study participants were able to quit ERT infusions at 24 weeks is potentially life-changing for thousands of people with Pompe. At this point in the study, it’s really the best news we could hope for at this early time.

There’s nothing negative about this interview, but there is certainly a lot riding on this trial. Many Pompe Disease patients are hopeful it will offer a “cure” for Pompe and possibly even reduce some symptoms that Myozyme/Lumizyme are typically not able to improve significantly (brain symptoms, for example).

Although many hope this will be something of a “silver bullet”. There are other gene therapy trials in the Pompe Disease treatment pipeline. Audentes Therapeutics in late July 2020 began recruiting patients for their gene therapy trial known as FORTIS.

Video via checkrare.com: