RGX-314 is our product candidate for the treatment of wet age-related macular degeneration (AMD). RGX-314 is being developed as a novel, one-time subretinal treatment for wet AMD that includes the NAV AAV8 vector encoding a gene for a monoclonal antibody fragment. The expressed protein is designed to neutralize vascular endothelial growth factor (VEGF) activity, modifying the pathway for formation of new leaky blood vessels and retinal fluid accumulation.
Wet AMD is characterized by loss of vision due to excess blood vessel formation between two layers of cells in the retina. This excess blood vessel formation results in fluid leakage that can result in physical changes in the structure of the retina and changes in vision. As this process becomes more severe, blindness can result from scar formation due to hemorrhaging.
Current ant-VEGF therapies require repetitive and inconvenient intraocular injections, typically ranging from every four to eight weeks in frequency, to maintain efficacy. Due to a variety of factors, including inconvenience and discomfort associated with frequent injections in the eye, patient compliance is a significant concern with anti-VEGF therapies. Patients often experience vision loss with reduced frequency of treatment.
An IND to support the initiation of a dose-escalation Phase I clinical trial of subretinally delivered RGX-314 in the U.S. in patients with wet AMD is active.
RGX-501 is our product candidate for the treatment of homozygous familial hypercholesterolemia (HoFH), which is designed to use the AAV8 vector to deliver the human low-density lipoprotein receptor (LDLR) gene to liver cells.
HoFH is a monogenic disorder caused by abnormalities in the function or expression of the LDLR gene. HoFH patients have very low levels or are completely deficient of LDLR, resulting in very high total blood cholesterol levels. This leads to premature and aggressive plaque buildup, life threatening coronary artery disease (CAD) and aortic valve disease.
The current standard of care in HoFH focuses on early initiation of aggressive treatment due to severe clinical effects of elevated LDL-C. Available therapies do not provide a cure and their use is limited due to tolerability and drug availability.
We believe that the liver is the preferred target organ for gene therapy of HoFH since LDLRs produced in the liver contribute to greater than 90 percent of the capture and breakdown of LDL, making the liver by far the most important LDLR producing organ.
We, together with trial sponsor University of Pennsylvania, are currently enrolling patients with HoFH in a Phase I/II clinical trial of intravenously administered RGX-501. RGX-501 has received orphan drug product designation from the FDA.
RGX-111 is our product candidate for the treatment of Mucopolysaccharidosis Type I (MPS I), which is designed to use the AAV9 vector to deliver the human α-l-iduronidase (IDUA) gene to the central nervous system (CNS). MPS I is a rare recessive genetic disease caused by deficiency of IDUA, an enzyme required for the breakdown of polysaccharides heparan sulfate and dermatan sulfate in the lysosomes of cells. Many patients develop symptoms related to glycosaminoglycan storage in the CNS, which can include excessive accumulation of fluid in the brain (hydrocephalus), spinal cord compression and cognitive impairment.
Current standard of care treatments cannot treat the CNS manifestations of MPS I and leave a significant unmet need for a method to safely achieve long-term IDUA reconstitution in the CNS.
Delivery of the enzyme that is deficient within cells in the CNS could provide a permanent source of secreted IDUA beyond the blood-brain barrier, allowing for long-term cross correction of cells throughout the CNS.
We expect to file an IND for RGX-111 for the treatment of MPS I in the first half of 2017 and expect to begin enrollment in a Phase I/II clinical trial in the second half of 2017. RGX-111 has received orphan drug product and rare pediatric disease designation from the FDA.
RGX-121 is our product candidate for the treatment of Mucopolysaccharidosis Type II (MPS II), also known as Hunter syndrome, which is designed to use the AAV9 vector to deliver the human iduronate-2-sulfatase (IDS) gene to the central nervous system (CNS).
MPS II is a rare, X-linked recessive disease caused by a deficiency in the lysosomal enzyme IDS. In severe forms of the disease, early developmental milestones may be met, but developmental delay is readily apparent by 18 to 24 months. Developmental progression begins to plateau between three and five years of age, with regression reported to begin around six and a half years.
Specific treatment to address the neurological manifestations of MPS II and prevent or stabilize cognitive decline remains a significant unmet medical need.
Delivery of the gene encoding the enzyme that is deficient within cells in the CNS could provide a permanent source of secreted IDS beyond the blood-brain barrier, allowing for long-term cross correction of cells throughout the CNS. We believe this strategy could also provide rapid IDS delivery to the brain, potentially preventing the progression of cognitive deficits that otherwise occur in Hunter syndrome patients.
Preclinical studies have demonstrated the potential therapeutic benefit of AAV9-mediated IDS gene delivery to the CNS through the cerebrospinal fluid to address neurological manifestations of MPS II. We intend to file an IND in mid-2017 to support the initiation of an early phase, dose-escalation clinical trial of RGX-121-based gene delivery via CNS administration in subjects with MPS II. RGX-121 has received orphan drug product and rare pediatric disease designation from the FDA.