GAINESVILLE, Fla., and CAMBRIDGE, Mass., Aug. 25, 2020 (GLOBE NEWSWIRE) -- Applied Genetic Technologies Corporation (NASDAQ:AGTC), a biotechnology company conducting human clinical trials of adeno-associated virus (AAV)-based gene therapies for the treatment of rare diseases, today announced that preclinical data validating the transgene (hRPGRco) that is being evaluated in the Company's ongoing Phase 1/2 clinical trial in patients with X-lined retinitis pigmentosa (XLRP) have been published in the July 15, 2020 print issue of Human Gene Therapy. The studies, which evaluated the safety and efficacy of hRPGRco and another XLRP transgene in a canine model of XLRP, demonstrated stronger expression of hRPGRco than the other transgene at all dose levels evaluated. Following subretinal administration in AGTC's proprietary rAAV2tYF vector, each of the XLRP transgenes corrected rod-cone opsin mislocalization, which are early markers of the disease, but the hRPGRco transgene demonstrated a broader therapeutic index. Study results also helped to guide the initial dosing in ongoing Phase 1/2 trial. As previously announced, AGTC expects to begin a Phase 2/3 clinical trial of its XLRP gene therapy candidate in the first quarter of 2021.
"Gene-based therapies contain multiple elements, and small differences in any one of those elements can have a significant impact on safety and efficacy," said Mark Shearman, PhD, Chief Scientific Officer of AGTC and an author on the publication. "We have shown our commitment to gene therapy through almost 20 years of experience and multiple clinical programs; this commitment demands that we conduct rigorous preclinical development work to ensure that we advance gene-therapy candidates that are optimized for safety and efficacy. These newly published preclinical data not only further validate the safety of our therapy but our choice of XLRP transgene for our clinical program."
The publication reports data from studies conducted in the RPGR-mutant canine model (XLRPA2), which has been validated as a model for human XLRP due to mutations in the RPGR gene. AAV vectors contained a "stabilized" version of the human RPGR gene (hRPGRstb), which is shorter than the wildtype DNA sequence, or a full-length version of the RPGR gene that has been codon optimized for improved expression and stability (hRPGRco). Both transgenes have previously been evaluated in the XLRPA2 model using an AAV5 vector. The current studies were conducted using AGTC's proprietary AAV2tYF vector, which is optimized for delivery to target cells within the retina. Safety was similar for the two transgenes. A key finding from the studies is that the AAV2tYF-hRPGRco vector resulted in higher RPGR gene expression compared with AAV2tYF-hRPGRstb and with AAV5-GRK1-hRPGRco. Additionally, the studies showed that while the mid-dose led to optimal correction of disease phenotypes, structural and functional rescue of photoreceptors was also achieved when treating at mid-stage disease with rAAV2tYFGRK1-hRPGRco at the lowest dose. This significantly expands therapeutic index and guided a starting dose for the ongoing Phase 1/2 clinical trial.
"Our focus on optimizing every aspect of gene therapy – including vector elements, routes of administration and manufacturing - differentiates AGTC from competitors," said Sue Washer, President and CEO of AGTC. "Our rigorous approach to developing best-in-class therapies is, we believe, the reason that our XLRP trial data to date, based on publicly released information, compares favorably with that reported by our competitors. With more than 100 patients enrolled in our collective clinical trials, studies have shown that each of our therapies have been generally safe and well-tolerated with no serious adverse events reported. We are currently enrolling additional patients into our expanded Phase 1/2 trial and look forward to initiating a Phase 2/3 trial in the first quarter of 2021."