FEATURED STUDY: PROCLAIM – A Study of PR006 with FTD-GRN

The PROCLAIM study, sponsored by Prevail Therapeutics, is evaluating safety and effectiveness of a one-time investigational gene therapy (PR006) intended to treat people diagnosed with a form of frontotemporal degeneration caused by mutations in the progranulin gene (GRN), referred to as FTD-GRN.

This Phase 1/2 clinical trial will also examine the effects of PR006 on progranulin protein levels in the plasma (the liquid component of blood) and in the cerebrospinal fluid (CSF; fluid from the area surrounding the brain).

Progranulin protein is a product of the GRN gene and is decreased in people with FTD caused by GRN mutations. PROCLAIM will test whether PR006 can increase progranulin levels and result in modification of the underlying disease process to possibly slow or halt progression of the disease.

Results from PROCLAIM will inform further clinical investigation and potentially allow approval of PR006 by the U.S. Food and Drug Administration (FDA) and the health authorities of other countries.

Please note that this glossary is available to help you understand the scientific terms used in this article. Glossary terms are shown here in bold the first time they appear.

FTD and GRN

Frontotemporal dementia (FTD) or frontotemporal lobar degeneration (FTLD) refers to a group of disorders caused by progressive degeneration of neurons in the brain's frontal lobes (the areas behind your forehead) or its temporal lobes (the regions behind your ears). These regions of the brain are important for decision-making, behavioral control, emotion, and language.

FTD is often inherited, with genetic forms making up to 20% of all FTD cases. Mutations in the GRN gene are a common genetic cause of FTD.

Patients with GRN mutations have significantly lower levels of progranulin protein, which is found in lysosomes or “recycling centers” in cells that break down cellular waste and excess proteins. Without enough progranulin, the lysosomes cannot effectively degrade or recycle proteins. This can lead to inflammation of the brain and neurodegeneration.

Available data from observational clinical studies as well as experiments in animal models of FTD support the idea that restoring progranulin levels may slow, halt, or possibly reverse the disease process.

There are no disease-modifying therapies available for patients with FTD, and current treatment consists of management of symptoms and supportive care.

The FDA designated PR006 an orphan drug in December 2019. Orphan Drug designation is granted to drugs or biologics intended to treat a rare disease or condition, which include those that affect fewer than 200,000 individuals in the United States. FTD is estimated to affect about 60,000 people. Last month the European Commission also granted orphan designation to PR006.

What is gene therapy?

Genes are stretches of DNA that contain instructions for making proteins, the essential building blocks of the cells in your body. Genetic differences, or "mutations," can result in the malfunctioning, reduction or complete loss of proteins necessary for important biological functions. In some cases, these mutations can lead to, or increase the risk of, certain diseases such as FTD-GRN.

Genetic testing enables individuals and their physicians to identify potential disease-associated mutations.

Gene therapy is a form of treatment that involves adding or modifying genetic material in a patient's cells, in most cases to introduce a healthy copy of a mutated gene. The majority of gene therapies for central nervous system (CNS) disorders are designed to be one-time and lifelong treatments.

How does PR006 work?

PR006, the therapy being evaluated in the PROCLAIM study, is composed of a carrier called a vector that is genetically engineered to deliver a normal copy of the GRN gene. The vector is called adeno-associated virus 9 (AAV9). These viruses are specially modified so they cannot cause disease in people, and the body’s immune system clears the virus after the gene enters the cell nucleus and the virus is no longer needed. Gene delivery with an AAV9 vector has a track record of efficacy and safety. AAV-based gene therapies have been successfully used in treatments for other serious illnesses, and the FDA has approved gene therapies for treating spinal muscular atrophy and an inherited form of blindness.

PR006 is an investigational gene therapy product, which means regulatory agencies like the FDA have not approved it for the treatment of FTD-GRN or any other indication. PR006 has not been tested previously in humans, but has been approved for use in clinical trials by the FDA. It has been tested in animal experiments (mice and non-human primates), where no PR006-related adverse events were observed at the doses that will be used in this clinical study.

Prevail announced on December 11, 2020, that the first person with FTD-GRN has received a dose of PR006.

“Dosing the first patient in our PROCLAIM clinical trial marks an important milestone in our efforts to advance a potentially disease-modifying treatment for patients with frontotemporal dementia with GRN mutations,” said Asa Abeliovich, M.D., Ph.D., founder and chief executive officer of Prevail. “We are excited to progress clinical development of PR006 and to bring forward a much-needed therapy for this rapidly progressing neurodegenerative disease.”

Eligibility and Protocols

The PROCLAIM study is seeking participants who:

• Are between 30 and 80 years of age
• Have been diagnosed with FTD with a disease-causing GRN mutation
• Are experiencing symptoms related to FTD (examples include personality changes or changes in language skills)
• Are using stable doses of background medications
• Are living in the community (i.e. not in a nursing home); although some levels of assisted living may be permitted
• Have a study partner – i.e., someone who is close to them, such as a family member or close friend – who can attend study visits with them
• Are able to safely undergo the procedure, in the study doctor’s opinion
• Have never before received a cell or gene therapy

Study participation will last for up to five years and will involve 20 visits to the study center, including one three-day visit, two or three days of which will be inpatient.

The procedure to administer PR006 is minimally invasive and has been used by neurosurgeons and neuroradiologists for many years. The investigational drug will be injected into the back of the head near the top of the neck, into an area near the brain called the cisterna magna, by a neurosurgeon or an interventional radiologist. This type of administration is designed to achieve maximal brain distribution.

Direct administration of PR006 into the cisterna magna reduces its exposure to the rest of the body, potentially minimizing the risk of side effects. This procedure will be done in the hospital under either general anesthesia or deep sedation. The neurosurgeon or interventional radiologist will use computed tomography scans (similar to X-rays) to safely guide the injection needle into the appropriate area.

All participants taking part in this study will also receive medications to reduce the risk of experiencing a reaction or other side effects during and after the injection.

As a part of baseline and follow-up visits, trial participants will undergo:

• blood draws
• electrocardiograms
• Magnetic Resonance Imaging (MRI; produces images of your brain) scans
• Magnetic Resonance Angiography (MRA; produces images of blood vessels in your head and neck) scans
• Dual-Energy X-ray Absorptiometry (DEXA; to assess bone density) scans
• lumbar punctures for CSF testing
• clinical scales to assess changes in cognition, behavior, language, and daily living.