Manufacturing Strategy Key to AGTC’s Next Steps for Gene Therapy Programs

As Applied Genetic Technologies Corp. takes the next steps in the development of its lead gene therapy candidate for inherited retinal disease, the company has fine-tuned its manufacturing process to not only produce material for the clinical trial, but also to provide a platform that’s scalable for production of large enough lots for commercialization.

The firm has also taken the step of forming a patient advisory council to open a communications channel with patients and caregivers.

In an exclusive interview with OIS Weekly, AGTC President and CEO Sue Washer described the company’s manufacturing strategy. She and Dave Knop, PhD, head of process development at AGTC, have already done a deep dive on the manufacturing process, publishing an article in the June issue of the trade journal BioProcess International.

Last month, after receiving written feedback from the Food and Drug Administration, AGTC reported it has revised the development plan for its potential treatment of X-linked retinitis pigmentosa (XLRP) caused by mutations in the RPGR gene. The revised plan includes immediate expansion of the current trial in parallel with the planned Phase II/III trial, which will be designed to evaluate sustained efficacy in patients with XLRP, an inherited condition that causes progressive vision loss in boys and young men.

Manufacturing ‘Well in Hand’
“We feel we have manufacturing well in hand,” Washer said. “We are very far along. Our process as described in the [BioProcess International] article is already at commercial scale. We are currently validating the assays required by the FDA for characterization and getting the process ready at our contractors to make the material for the Phase II/III trial. It is the same process we would use commercially.”

She explained that AGTC is taking a novel approach to manufacturing. Other manufacturers in the gene therapy space use a series of flat plastic surfaces, in some cases arranged into stacks or semi-automated machines, known as flat stock, to grow cells on. “That really constrains you and increases your cost because of how much factory space and personnel you need to manipulate all those plastic surfaces or machines,” Washer said.

AGTC’s “highly scalable” process uses a stirred-tank bioreactor to make clinical trial material. “Which means,” Washer continued, “you can make that stirred tank very, very large in a smaller footprint with fewer people to monitor it than with flat stock.”

“It will certainly get factored into the cost of goods sold, and it could be a distinct advantage in either larger markets or in indications where a higher dose is required,” she said.

The manufacturing process is also capable of making material for AGTC’s two active trials in achromatopsia (ACHM CNGB3, and ACHM CNGA3).

Acting on FDA Feedback
The written FDA response on the XLRP program addressed the design and execution of a registration trial and future regulatory submissions.

“We are pleased with the productive feedback from the FDA and are modifying our development program based on their recommendations to advance our XLRP gene therapy candidate,” Washer stated in a press release.

AGTC is expanding the ongoing Phase I/II trial immediately and plans to dose approximately 20 patients in two masked dosing arms to collect additional functional data, including a mobility test added as a supplemental endpoint. The company expects to begin dosing in Q4.

For late-stage studies, the FDA indicated in its written feedback, which is consistent with how others in the XLRP gene therapy space are analyzing data, that a change in visual sensitivity of 7 decibels or greater in at least five loci would be clinically meaningful. AGTC previously reported visual sensitivity as a mean over an entire treated area, but believes multiple patients already evaluated in the ongoing Phase I/II trial would meet the FDA’s definition.

The revised Phase II/III trial design is also expected to include two masked active arms in addition to a control group, with visual sensitivity as the primary endpoint and several supplemental endpoints such as the mobility test. AGTC expects to begin this trial in Q1 2021.

Patient Advisory Council
The patient advisory council, spearheaded by Jill Dolgin, PharmD, head of patient advocacy at AGTC, has eight members. Four are from the Foundation Fighting Blindness (FFB): Brian Mansfield, PhD, executive VP of research and interim chief scientific officer; Todd Durham, PhD, VP for clinical outcomes research; Michelle Glaze, associate director of professional outreach and a retinitis pigmentosa patient; and Richard Faubion, senior director of development who also has XLRP and is a stem-cell trial participant.

Two are from Sofia Sees Hope, a non-profit that supports people with Leber congenital amaurosis (LCA) and inherited retinal diseases: President and Founder Laura Manfree, who’s also a parent of a child with LCA; and Alison Lynch, a disabilities attorney and an achromatopsia patient and non-gene therapy clinical trial participant.

Other members are Fighting Blindness Canada Health Information Officer Shari Shaw, MHSc, who also has RP, and Retina International CEO Avril Daly, who’s also VP and board member of the European Organization for Rare Diseases, and a person with RP.

Said Dr. Mansfield of the FFB: “Having the patient’s perspective at the center of clinical drug development is a crucial component for addressing the unmet needs of patients within the inherited retinal diseases community.”