AGTC president and CEO Sue Washer

Buoyed by positive 12- and preliminary 24-month data, Applied Genetic Technologies Corp. (AGTC) says it is advancing its gene therapy candidate for X-linked retinitis pigmentosa (XLRP) into a Phase II/III trial as well as an expanded Phase II study that over the next 18 months. Both trials are intended to generate results strong enough to file for regulatory approvals.

AGTC president and CEO Sue Washer said the company was moving ahead with two clinical studies further assessing its adeno-associated virus (AAV)-based XLRP gene therapy, named rAAV2tYF-GRK1-RPGRco: The Phase II/III VISTA trial (NCT04850118), which had yet to begin recruiting patients at deadline; and a Phase II expansion study called SKYLINE (NCT03316560).

Washer spoke to GEN Edge days after AGTC released 12-month data from seven patients in one cohort (Group 5) and four in another (Group 6) who were treated with the highest doses of the gene therapy in its ongoing Phase I/II trial (NCT03316560). That data showed a 50% response rate as four of eight patients (six from Group 5, two from Group 6) met the inclusion criteria for the two upcoming trials by showing at least a 7-decibel (dB) improvement in at least 5 loci.

The 12-month data included Best Corrected Visual Acuity (BCVA) findings that were consistent with those generated at six months after treatment by groups 2, 4, 5, and 6. Full 12-month results from the Phase I/II trial are set to be presented at the American Academy of Ophthalmology Annual Meeting in November 2021.

AGTC also released 24-month data from three of seven patients in a third cohort (Group 4) of the Phase I/II trial whose data were available for analysis 24 months following treatment, showing preliminary evidence of response durability. Two of the three responded 12 months after treatment—one showed a 7-dB improvement in at least five loci, while the other showed statistically significant improvement in retinal sensitivity in their treated eye compared with their untreated eye after 12 months.

Both Group 4 responders continued to respond to treatment after 24 months.

“We are the first to report in the XLRP space this length of durability of response. We think that that’s a significant advancement and differentiator for us,” Washer said.

The 50% response rate is especially significant as it was maintained from earlier studies and was the rate used in trials of AGTC’s closest competitor product, Roche-owned Spark Therapeutics’ gene therapy Luxturna® (voretigene neparvovec-rzyl), which was approved in December 2017 to treat children and adults with a rare inherited form of blindness (RPE65 mutation-associated retinal dystrophy). “It’s the response rate that we have powered the VISTA trial to pick up. Everything is really coming together, we believe.”

AGTC hopes to accelerate that differentiation in the data it will generate from the SKYLINE and VISTA trials. The company plans to provide SKYLINE trial results from the three-month masked interim analysis in the fourth quarter, followed by 12-month results in the third quarter of 2022. By the fourth quarter of 2022, AGTC plans to release results from a six-month masked interim analysis of VISTA data.

Success and failure

AGTC is among several developers of XLRP gene therapies that are now in clinical trials.

Janssen Pharmaceuticals has partnered with MeiraGTx to develop its XLRP gene therapy AAV-RPGR, while Biogen’s candidate, cotoretigene toliparvovec (BIIB112), has advanced to the Phase II/III XIRIUS trial (NCT03116113). MeiraGTx and Janssen presented 12-month data from their ongoing Phase I/II trial (NCT03252847) in November showing sustained statistically significant vision improvement in the study’s dose escalation phase one year after treatment.

However, on May 14, Biogen acknowledged that cotoretigene toliparvovec missed the primary endpoint of the XIRIUS trial by failing to show statistically significant improvement in the proportion of treated study eyes with ≥7-dB improvement from baseline at ≥5 of the 16 central loci of the 10-2 grid assessed by Macular Integrity Assessment (MAIA) microperimetry 12 months after treatment, compared to the study eye of patients randomized to the untreated control group.

However, investors seemed to dismiss the news, as Biogen shares only dipped 0.5% the day of the announcement ($280.21 from $281.71).

“This is clearly disappointing news, but this product has not been a focus for investors, so we wouldn’t expect much of a meaningful move in the stock,” Marc Goodman, a managing director and senior research analyst covering Neuroscience and Ophthalmology at SVB Leerink, explained in a research note. “It was never clear to us how significant this program would have been commercially, given that a few other companies have also been pursuing this orphan opportunity.”

SVB Leerink has maintained its “Outperform” rating on Biogen shares, and made no changes to its earnings forecasts or $380 12-month price target based on the XLRP news. Goodman noted that cotoretigene toliparvovec showed positive trends across several secondary endpoints, such as a clinically relevant measure of visual acuity.

Addressing analysts after AGTC’s release of results for its fiscal third quarter 2021 on Monday, Washer cited four key differences with Biogen’s XLRP program that AGTC reasons will ultimately lead it to greater late-stage success without the dosage safety problems encountered by some gene therapy developers, most recently last month:

  • AGTC said it designed and “exhaustively” tested its product construct in both non-human primates and naturally occurring dog models early in development to ensure it selected the most appropriate components, including a proprietary capsid, and defined the most appropriate dose range allowing for higher-level dosing.
  • The Phase I/II data showed a more robust safety profile over all doses and biological activity over a wider dose range, including a statistically significant improvement in BCVA.
  • The Skyline and Vista trials will analyze activity over a wider area of the retina in patients with better baseline characteristics, using a proprietary algorithm to define patients most likely to respond.
  • AGTC has added a secondary endpoint using the Ora Visual Navigation Challenge (Ora-VNC™), used in clinical trials worldwide to evaluate gene therapies targeting inherited retinal diseases.

Deeper penetration

“The primary difference between our products and that of Biogen Nightstar is the capsid,” Mark Shearman, PhD, AGTC’s chief scientific officer, said on the conference call.

Shearman explained that AGTC’s capsid showed deeper penetration into primate photoreceptors and expressive transgene than those of Biogen, or of Janssen/MeiraGTx: “Our capsids have about a two-to-threefold improvement in that ability, so a greater expression level.”

The primate and dog model studies, Shearman said, safely allowed AGTC to safely reach the maximum tolerated dose, controlled by concomitant use of steroids, and allowed it to determine and show activity at multiple doses, including those given to patients in cohorts 5 and 6.

This “puts us in a great position to be able to really know what the most effective dose is and know and how confident that that can be administered safely,” Shearman added.

AGTC says the safety profile is another differentiator from competitors. The company noted that data from all 28 patients in the Phase I/II trial’s six dose groups out to 24 months showed no dose-limiting inflammatory responses, including clinically significant inflammation that were not manageable with steroids.

The SKYLINE trial is designed to assess to what extent each of the two doses, both of which suggested potential benefit in some participants enrolled in the original Phase 1/2 study, demonstrate improvement in a participants’ vision and other symptoms of XLRP. The VISTA trial is intended to evaluate the effect of the gene therapy on symptoms of retinitis pigmentosa in additional patients with XLRP.

To support clinical phase product release for the VISTA trial, AGTC has made improvements to its manufacturing process, as well as developed and validated a novel expression assayboth of which it detailed last week.

In one abstract (No. 806) presented during the recent American Society of Gene & Cell Therapy (ASGCT) Annual Meeting, AGTC compared transgene expression between vectors produced with its original and improved processes. AGTC said it optimized its clarification and affinity steps, and substituted an anion exchange column for the original cation exchange column—a change that improved its full-to-empty capsid ratio from 30% to greater than 80%. The company also said its manufacturing changes also reduced process residuals (Host cell DNA and Protein), and improved its ratio of infectious particles (< 4.0 total particles/infectious particle).

“In early research, the manufacturing process can result in vectors that either have the intended gene within the capsid; that’s a “full.” Sometimes the capsid package, the vector packages, and the DNA is not inside; that’s an “empty,” Washer explained. “Obviously the empty doesn’t help the patient at all. We’ve made several improvements to our process and we’re really closer to 90% or more full capsids, which means that we don’t have any of those extra empties around to cause issues of any kind.”

Measuring vector’s mRNA expression

In another ASGCT abstract (No. 884), AGTC also reported the development and validation of an in vitro cell-based assay designed to measure hRPGRco (codon-optimized human retinitis pigmentosa GTPase regulator) mRNA expression from AGTC’s XLRP vector, rAAV2tYF-GRK1-RPGRco. (The assay was qualified for use according to International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines based on sensitivity, specificity, accuracy, precision, real-time qPCR linearity, and total assay linearity.)

AGTC also disclosed it plans to lease a 21,000-square-foot, build-to-suit cGMP manufacturing and quality control facility adjacent to its headquarters facility in Gainesville, FL, to prepare for anticipated late-stage development of its XLRP program and another clinical program focused on treating achromatopsia.

The facility is also intended to accelerate AGTC’s plans to file a BLA for the XLRP gene therapy and launch it commercially upon FDA approval, as well as support faster advancement of the company’s pipeline, provide supply chain redundancy, and reduce manufacturing risk. Buildout is expected to be completed in the second half of 2022, according to the company.

To fund the internal manufacturing expansion, AGTC restructured an existing up-to-$25 million loan agreement with Hercules Capital through a second term loan advance of $10 million, and an extension of the agreement’s interest-only period and loan maturity date to March 31, 2022 and April 1, 2024, respectively—dates that can be further extended if AGTC achieves milestones. AGTC also won the right to receive an additional loan advance of up to $5 million before April 1, 2022, or before January 1, 2023 if unspecified conditions are satisfied.

The restructured loan plus $111 million in cash, cash equivalents and investments as of March 31 are believed sufficient to fund company operations into 2023, according to AGTC.

AGTC finished its fiscal-year third quarter ending March 31 with a net loss of $45.7 million, versus $31.4 million for the nine months ending March 31, 2020. Most of the higher net loss reflects a $9.1 million increase in R&D expenses due to increased external XLRP spending for planned manufacturing, clinical site preparation and other activities related to the SKYLINE and VISTA trials.

The R&D expense was partially offset by decreased spending on AGTC’s achromatopsia program, through which the company is developing separate gene therapies for achromatopsia caused by a mutation in the CNGB3 gene, and by a CNGA3 gene mutation. Trials for each gene therapy are in progress, with 12-month data from adult patients in both trials expected later this quarter, and three-month data from children in both trials, in the fourth quarter.

“What we would like to see is continuation of the response rate that we were able to show with the six months data, such that the 12 months data matches the six month data,” Washer said. “Then, we’ll be able to make plans to move the product forward.”

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