The U.S. Food and Drug Administration (FDA) has granted the National Institutes of Health’s National Center for Advancing Translational Sciences (NCATS) a Rare Pediatric Disease (RPD) designation for AAV9-hPCCA (NCATS-BL0746), an investigational gene therapy for the treatment of propionic acidemia (PA) resulting from the deficiency of propionyl-CoA carboxylase (PCC) due to mutations in its alpha subunit (PCCA).
The RPD designation is an important milestone in the process of securing a Priority Review Voucher (PRV), an incentive to expedite drug development. To qualify for the RPD designation, applicants must provide FDA data that suggests that an experimental drug may be effective in a rare disease that primarily affects a pediatric population. The FDA finalizes the RPD designation and RPD product designation on the basis of the information available at the time of marketing application, and awards a PRV to the sponsor of a qualifying approved application. PRV holders can use the PRV to expedite the FDA review process for a future marketing application or sell the voucher to a different sponsor. This is an incentive for orphan drug development for rare pediatric diseases because either option can result in a significant financial windfall.
Patients with PCCA-related PA cannot break down dietary protein, which leads to chronic, sometimes life-threatening conditions, including metabolic imbalance, cardiomyopathy, kidney disease, and other serious complications. Charles Venditti, M.D., Ph.D., Chief of the Metabolic Medicine Branch of the National Human Genome Research Institute, has studied PA and its potential treatments for many years. “The RPD designation speaks to the promise of AAV9-hPCCA for patients living with PCCA-related PA. If our planned clinical trial for AAV9-hPCCA is successful, an RPD designation could make it much more likely that all patients will be able to access this gene therapy.”
AAV9-hPCCA is one of four adenovirus-associated virus (AAV) gene therapies that will be developed in NCATS’ Platform Vector Gene Therapy (PaVe-GT) pilot project. PaVe-GT aims to increase the efficiency of clinical trial startup for gene therapies. AAV is a viral vector that has been used in multiple gene therapy clinical trials and is potentially useful for a significant percentage of genetic diseases.
“A major goal of PaVe-GT is to demystify the regulatory process for AAV gene therapies,” explains Elizabeth Ottinger, Ph.D., Acting Director and Head of Project Management of the NCATS Therapeutic Development Branch. “The PaVe-GT team has distilled and organized our insights on how to compile two important and highly interrelated designation applications: the RPD designation, and the Orphan Drug Designation (ODD). In coming weeks, we anticipate publishing a white paper with broadly useful advice about how we developed our applications for these designations.” Earlier this year, NCATS announced that FDA granted an ODD for AAV9-hPCCA.
“A unique element of PaVe-GT is our commitment to make our program results and regulatory documents publicly available,” notes P.J. Brooks, Ph.D., Acting Director of the NCATS’ Division of Rare Diseases Research Innovation. “In conjunction with the release of the upcoming white paper, we also anticipate releasing the designation requests that were submitted to the FDA. We believe that these materials will be useful to any party interested in developing gene therapies and will be especially useful for groups interested in developing gene therapies for diseases with very small populations.”
3/30/23 Update: Visit the PaVe-GT Resources page for RPD Designation resources, including the lightly redacted designation request for AAV9-hPCCA, and an RPD Designation request template.
The U.S. Food and Drug Administration (FDA) has granted the National Institutes of Health (NIH)’s National Center for Advancing Translational Sciences (NCATS) an orphan drug designation for AAV9-hPCCA (NCATS-BL0746), an investigational gene therapy for the treatment of propionic acidemia resulting from a deficiency of Propionyl-CoA Carboxylase, alpha subunit (PCCA). Propionic acidemia is an inherited metabolic disease. Patients with propionic acidemia cannot break down dietary protein, which leads to chronic, sometimes life-threatening conditions, including metabolic imbalance, cardiomyopathy, kidney disease, and other serious complications. Some patients are offered liver transplantation as a treatment because dietary and medical management are often not effective.
AAV9-hPCCA is a novel gene therapy candidate that uses adenovirus-associated virus serotype 9 (AAV9), a viral vector that has been used in multiple gene therapy clinical trials to deliver therapeutic transgenes to diverse tissues and cell types. It is potentially useful for a significant percentage of genetic diseases.
AAV9-hPCCA is one of four gene therapies that will be developed in NCATS’ Platform Vector Gene Therapy (PaVe-GT) program, a pilot project that is aimed at increasing the efficiency of clinical trial startup for gene therapies. AAV9-hPCCA and the three other gene therapies in the PaVe-GT program will all use the same capsid and the same manufacturing methods to test whether holding those factors constant would increase the efficiency of gene therapy trial startup. Notably, since all collaborating partners are within the NIH, the PaVe-GT program can test this in a transparent manner. Regulatory materials from the program will be made publicly available, so they can be used to benefit subsequent AAV gene therapy efforts.
Orphan drug designations confer important benefits for rare disease drug developers, including exemption from user fees, tax credits, and extended market exclusivity. However, the PaVe-GT team also had other considerations in mind when it applied for this designation.
“Our goal,” explained P.J. Brooks, Ph.D., Acting Director of NCATS’ Division of Rare Diseases Research Innovation, “is to put the broadly relevant results, materials, and regulatory filings from the PaVe-GT program into the public domain. By sharing a successful orphan drug designation application with the public, we can reduce the amount of time it takes for other scientific teams to produce orphan drug designation applications of their own, an activity that can be particularly burdensome for parties interested in developing gene therapies for diseases with very small populations.”
“AAV is a gene therapy platform that holds great promise for many monogenic diseases, including rare diseases that are too rare to attract traditional commercial interest,” noted Elizabeth Ottinger, Ph.D., Deputy Director for Programs of the NCATS Therapeutic Development
Branch. “However, gene therapy developers for extremely rare diseases often have very limited experience navigating the regulatory process. Access to a successful orphan drug designation application will be very helpful to groups who are advancing their first orphan candidate.”
The PaVe-GT team, a synergistic collaboration across four NIH Institutes, anticipates releasing the AAV9-hPCCA orphan drug designation application and the FDA’s response letter to the public in 2022.
Charles Venditti, M.D., Ph.D., a Senior Investigator in the Metabolic Medicine Branch of the National Human Genome Research Institute, led the scientific team that identified the AAV9-hPCCA gene therapy candidate. “Receiving an orphan drug designation for AAV9-hPCCA is an important milestone for patients with PCCA, but there are many diseases that could benefit from a PaVe-GT approach,” Dr. Venditti said. “It’s time to demystify and streamline important regulatory processes. We’re proud that other scientific teams will be able to model their orphan drug designation applications after the application submitted for AAV9-hPCCA.”
“In addition to releasing our application to the public, the PaVe-GT team is preparing a paper with tools and required information for navigating orphan drug designation applications,” explained Dr. Ottinger, who leads project management of all four PaVe-GT gene therapies as part of the NCATS Therapeutics for Rare and Neglected Diseases program. “We are 100% committed to shifting the learning curve and increasing the efficiency of gene therapy development for rare diseases.”
3/30/23 Update: Visit the PaVe-GT Resources page for ODD Designation resources, including the lightly redacted designation request for AAV9-hPCCA, and an ODD Designation request template.