AGTC president and CEO Sue Washer

Gene therapy developer Applied Genetic Technologies Corp. (AGTC) has expanded its pipeline of orphan disease treatments in recent weeks by partnering with Otonomy to develop an early preclinical candidate for congenital hearing loss, and announcing Stargardt disease as the target of its second preclinical ophthalmology program.

Ophthalmology has been the initial focus of AGTC, which in September showed promising results in ongoing clinical trials for gene therapy candidates in X-linked retinitis pigmentosa (XLRP) and achromatopsia based on mutations in the ACHM CNGB3 and ACHM CNGA3 genes. The company also has preclinical programs in other ophthalmology and otology indications, as well as in optogenetics and adrenoleukodystrophy (ALD).

AGTC and Otonomy agreed recently to co-develop and co-commercialize an AAV-based gene therapy designed to restore hearing in patients with sensorineural hearing loss caused by a mutation in the gap junction protein beta 2 gene (GJB2), through a collaboration whose value was not disclosed.

“Genetic hearing loss was very interesting to us because it’s an area of unmet need. There really has not been any work or new help for people with hearing loss since the advent of hearing aids and cochlear implants, which happened decades ago,” AGTC president and CEO Sue Washer told GEN. “There are millions of people throughout the world with poor hearing that affects their quality of life and their job choices, their living choices. And we really want to be in areas with unmet need.”

GJB2 mutations account for approximately 30% of all genetic hearing loss cases, representing the most frequent cause of severe-to-profound congenital hearing loss.

GJB2 encodes connexin-26 expressed in cochlear support cells, forming gap junctions that control potassium homeostasis, which is critical for the survival and function of hair cells and normal hearing. Mutations in GJB2 impair gap junctions and cochlear homeostasis leading to hair cell dysfunction and hearing loss. GJB2 gene therapy is designed to restore functional gap junctions and improve hearing by preserving hair cells.

AGTC has released positive preliminary three-month dose-expansion data from seven centrally dosed patients treated with its X-linked retinitis pigmentosa (XLRP) gene therapy candidate showing improvement in 50% of those patients. The photo shows microperimetry results within the treated area as a heat map for the mid-dose responder, which according to AGTC indicated meaningful improvements in visual sensitivity three months after treatment, compared to the untreated eye and compared to baseline. [AGTC]
“Many of the cell types that are in the eye are the same kinds of cells that are in the ear, in that in the eye, waves of light are transferred to electrical signals that the brain can understand. In the ear, waves of sound are turned into electrical signals that the brain can understand,” Washer said.

After carrying out primary research into targeting gene therapy to cells in the ear, Washer said, AGTC connected with Otonomy and concluded it could bring treatments to market faster by matching the know-how it gleaned from that research, plus its gene therapy expertise, with Otonomy’s clinical expertise and familiarity with clinicians and surgeons specializing in ear disease.

AGTC will provide all design work for the vector to be used in the gene therapy it plans to develop with Otonomy, as well as research and animal models, all manufacturing for preclinical and clinical studies, and commercial manufacturing should the collaboration succeed as planned.

“In the early research that we did, we were looking broadly about how to target into different cells into the eye, whether they were support cells or hair cells, or around basal route ganglia cells,” Washer said. “All of that work we did on how to target specifically into the ear, what delivery methods, surgical methods to use to get to the different parts of the ear. We’re able to use that expertise very specifically in our collaboration with Otonomy.”

Targeting Stargardt disease

The Stargardt-targeting gene therapy candidate will use AGTC’s dual-vector adeno-associated virus (AAV) vector technology, for which the company has shown positive proof-of-concept expression data in non-human primates (NHPs).

Stargardt disease is the most common form of inherited macular degeneration, resulting most often from mutations in the ABCA4 gene. However, the DNA sequence encoding the ABCA4 protein exceeds the payload capacity of AAV vectors, a longtime challenge in developing gene therapies for the disorder.

AGTC’s technology is designed to deliver larger proteins like ABCA4 by dividing the coding sequence into two separate AAV vectors. Once inside the cell, the two DNA fragments recombine to form the complete coding sequence, producing full length, functional ABCA4 protein.

A dual-vector system was shown earlier this year to be safe and to offer therapeutic benefit in a mouse model of Stargardt disease by William Hauswirth, PhD, at the University of Florida, a longtime academic collaborator with AGTC, and colleagues at the University of British Columbia.

AGTC researchers optimized the vectors used by Hauswirth for administration to NHPs. In a 13-week study, the researchers prepared a subretinal injection of AAVs encoding the N-terminal fragment and C-terminal fragment of human ABCA4, which was tagged to distinguish it from the naturally occurring NHP ABCA4 protein.

The tagging enabled the researchers to clearly detect full length recombinant human ABCA4 protein in tissue punches harvested from inside the subretinal bleb, but not in the untreated surrounding tissue, which according to AGTC confirmed the specificity and effectiveness of the vector administration.

“An important milestone”

“AGTC’s demonstration that this approach is safe and results in ABCA4 protein expression in NHPs following subretinal injection of their optimized vectors is an important milestone in advancing gene therapy for Stargardt disease toward the clinic,” Hauswirth said in a statement.

Hauswirth is professor of ophthalmology and the Maida and Morris Rybaczki eminent scholar chair in ophthalmic sciences in the department of ophthalmology at the University of Florida.

Based on the NHP study results, Washer said, AGTC will continue development of its optimized dual vector system for the treatment of Stargardt disease.

“Our Stargardt disease program underscores our ability to leverage our expertise in AAV vector and genome engineering to expand AAV gene therapy into new indications that require delivery of larger DNA payloads,” Washer added.

AGTC sees similarities in the types of cells the company is targeting in the eye, ear, and CNS.

“What we’re doing is leveraging our understanding of differentiated neurons, whether they are neurons specialized in the CNS, neurons specialized in the ear, or neurons specialized in the eye,” Washer explained. “We’re leveraging our base understanding of how to target and correct that type of cell by going into these three similar areas.”

AGTC’s most advanced programs have been in ophthalmology. In September, the company disclosed positive data from its ongoing Phase I/II trial in patients with XLRP, showing stabilization of decline in the peripheral vision, improvement in central vision, and a favorable safety profile.

In XLRP, the company released six-month topline interim efficacy results in September from 10 patients (eight dosed peripherally and two dosed centrally), plus preliminary three-month data from seven centrally dosed patients. Eight patients who were dosed peripherally showed stable visual function at six months, while measurable improvements were seen in visual sensitivity for four of eight evaluable centrally dosed patients.

In achromatopsia, safety data from 27 patients released in September showed a favorable profile for each of the ACHM candidates. As a result, the study’s Data Safety Monitoring Committee (DSMC) has supported continued dose escalation and dosing of pediatric patients. One of three patients at the middle dose level in each trial and two of three patients at the high dose level in the ACHM B3 trial have shown clinically meaningful improvements in light discomfort, defined as greater than one log lux change from baseline at three months.

Twelve-month data from the XLRP and achromatopsia trials is set to be released in 2020.

AGTC employs 88 people—60% at its Gainesville, FL, headquarters; the rest in Cambridge, MA. “We expect that to grow into the mid-90s over the next several months,” Washer said. “Based on the data release that we communicate to [Wall] Street over the next several months, we would make new forecasts as to the headcount that we needed to be able to execute on those pivotal trials.”

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