Applied Genetic Technologies Corp. (AGTC) says it will launch its planned Phase II/III trial of its gene therapy candidate for X-linked retinitis pigmentosa (XLRP), caused by mutations in the RPGR gene, in the first quarter of 2021 after updating its development plan to reflect FDA feedback.

The FDA told AGTC to change its primary endpoint to a change in visual sensitivity of 7 decibels or greater in at least 5 gene loci, calling the revised endpoint clinically meaningful —  consistent with how other XLRP gene therapy developers are analyzing data. AGTC previously reported visual sensitivity as a mean over an entire treated area—a standard that had been applied to its ongoing Phase I/II trial (NCT03316560) of the gene therapy candidate.

AGTC CEO Sue Washer told GEN the change will not hurt the development program, despite the start of the trial being pushed back a few months from AGTC’s earlier estimate of a planned launch by the end of 2020.

“In the grand scheme of things, we just needed to adjust for statistics, to account for the revised endpoint that the FDA requested. But we think that the delay is marginal,” Washer said.

Washer added that no new testing will be needed for patients evaluated to date in the Phase I/II trial. AGTC believes multiple patients already assessed would meet the FDA’s revised standard; the company won’t specify how many until it discloses that within its Form 10-K annual regulatory filing in September.

“We’ve done all the work. It’s just a different way of analyzing the exact same data set,” Washer said. “There’s no new testing to be done with the patients. There’s no new data collection. It’s just how you crunch the numbers.”

Washer noted that visual sensitivity had never been used formally by a product to be approved by the FDA: “It’s just an evolution of really applying an endpoint that was guided by the FDA, that was theoretically an approvable endpoint, but had never been used.

“As the FDA has seen more and more data with visual sensitivity, as people have proposed it in clinical trials, I just think it’s the natural evolution of understanding and what they feel comfortable with as being clinically meaningful in the analysis,” Washer added.

AGTC’s 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 that include a mobility test.

Expanding Phase I/II Trial

In parallel with the launch of the Phase II/III trial, AGTC said, it will also expand the Phase I/II trial by planning to dose approximately 20 patients in two masked dosing arms to collect additional functional data, including a mobility test that will serve as a supplemental endpoint. That would nearly double the patient population of the non-randomized, open-label, dose escalation study, trial, which has an estimated enrollment of 30.

Last month, researchers from AGTC and the University of Pennsylvania published preclinical data in Human Gene Therapy showing validation of the transgene hRPGRco, which is being evaluated in the Company’s ongoing Phase 1/2 clinical trial in patients with XLRP. The studies, which evaluated the safety and efficacy of hRPGRco and another XLRP transgene, hRPGRstb, in a canine model of XLRP, showed hRPGRco to have stronger expression at all dose levels evaluated. Following subretinal administration in AGTC’s proprietary rAAV2tYF vector, each XLRP transgene corrected rod-cone opsin mislocalization, but hRPGRco demonstrated a broader therapeutic index.

Human Gene Therapy is published by GEN publisher Mary Ann Liebert Inc.

AGTC released positive six-month data last January from 17 of 25 patients in the Phase I/II trial. The data, according to AGTC, showed durable improvement in visual function in patients six months after being treated centrally with the gene therapy candidate, reinforcing positive six-month topline interim efficacy results the company released in September 2019.

The additional dosing is expected to start in the fourth quarter.

AGTC is one of three developers of gene therapies targeting XLRP. Last month, MeiraGTx released Phase I/II six-month data from its ongoing Phase I/II MGT009 clinical trial (NCT03252847) of AAV-RPGR, the XLRP candidate it is co-developing with Janssen Pharmaceuticals.

MeiraGTx’s data showed significant improvement in retinal sensitivity in three patients treated with the low dose, and four treated with the intermediate dose, of AAV-RPGR, following assessment with two perimetry approaches (static perimetry and microperimetry) and three analysis metrics (mean retinal sensitivity, central 30° hill-of-vision volumetric measure (V30), and pointwise comparison).

But at the highest dose, inflammatory responses were seen in two of three patients, which according to MeiraGTx may have been associated with decreased activity of AAV-RPGR in these patients—and was effectively managed with an extended steroid protocol.

The high-dose inflammation was “something that has not been seen with AGTC, despite relatively similar dosing range,” Matthew Luchini, biotechnology analyst at BMO Capital Markets, noted in a report to investors. “We believe AGTC’s ability to dose higher given absence of secondary inflammatory response may give the company more flexibility in development.”

Also developing an XLRP gene therapy is NightstaRx, a Biogen Company. Biogen acquired NSR-RPGR (since renamed BIIB112) when it purchased Nightstar Therapeutics for approximately $800 million in a deal completed in June 2019. BIIB112 is in an ongoing Phase II/III trial (NCT03116113) with an estimated enrollment of 63 participants, and an estimated primary completion date of March 2021.

“While all three late-stage gene therapy companies have shown positive signals on efficacy, AGTC has not seen evidence of secondary inflammation,” Kristen Kluska, Equity Research Analyst with Cantor Fitzgerald, reported in an investor note. “Based on the information disclosed thus far, we remain confident that AGTC could have a potential first-and best-in class asset for XLRP.”

Visual Acuity Data

Joseph Pantginis, PhD, Managing Director of Equity research and a Senior Healthcare Analyst with H.C. Wainwright & Co., observed in his investor note that despite the reported positive changes in visual sensitivity, MeiraGTX provided no data on visual acuity, and no improvements in visual acuity were observed with NSR-RPGR as well—while AGTC in January reported six-month data showing that all nine patients treated centrally with AGTC’s gene therapy candidate, sometimes referred to as AGTC-501, had stable or improving visual acuity, with 78% seeing a 5 letter or more improvement.

“AGTC’s observations are unprecedented and may be due to the efficient delivery, localization and expression of the vector carrying the RPGR gene. Should AGTC’s data be confirmed, we believe this result could set AGTC-501 far apart from competition moving forward,” Pantginis wrote.

This fall, Washer said, AGTC will report long-term data on its original dose cohorts, as well as six-month data on its top two dose cohorts. The Phase I/II trial divides participants into six groups given varying dose levels of the gene therapy, and a seventh group treated with the maximum tolerated dose as determined by the first six.

The FDA provided AGTC with comprehensive written feedback regarding the design and execution of a registration trial and future regulatory submissions in lieu of a traditional in-person meeting, likely due to limitations imposed by COVID-19.

Washer said AGTC is proceeding as planned with manufacturing, clinical site preparation and other activities to enable initiation of late-stage studies as soon as possible.

“We believe we have the potential for a best-in-class product when important factors such as visual sensitivity improvements, BCVA and safety are considered, which could provide meaningful benefit to patients with XLRP who today have no treatment options,” Washer stated.

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