Strongly favorable six-month data disclosed on Jan. 9 by Applied Genetic Technologies Corp. (AGTC) from its ongoing phase I/II program with an adeno-associated virus (AAV) gene therapy for X-linked retinitis pigmentosa (XLRP) did more than provide a whopping stock boost. They also lifted investor confidence the Gainesville, Fla.-based firm’s approach and laid the groundwork for a solid pivotal trial – due to start by the end of this year – in the challenging disease.

“Now that we have the data and we have a clear set of responders and nonresponders, we’re really digging into those baseline characteristics” of patients, CEO Susan Washer said during a conference call with investors. Until the analysis finishes the company is “not prepared to make a full statement,” she said. “But we're hopeful that we can pick out that kind of information because it will be very helpful to us in designing the pivotal trial.”

The results show that patients treated centrally turned up durable improvement in visual function six months after dosing, an outcome that reinforces the promising efficacy and safety results reported in September 2019. Data from 17 of the 25 patients were reported then and the treatment demonstrated a favorable safety profile. Of the 17, eight peripherally treated patients showed stable visual function through six months and nine centrally treated patients showed improvement in visual function as measured by microperimetry and/or best corrected visual acuity (BCVA) through three months.

At the six-month time point for the same nine patients, measurable improvements were found in visual sensitivity for four of the evaluable eight subjects – the same four discussed in September. Patients are defined as responders with improvement in visual sensitivity within the treatment area that is beyond the testing variability on at least two separate test dates. All nine patients treated centrally also had stable or improving visual acuity, with 78% chalking a five-letter or more improvement, a result not attained in other XLRP trials, AGTC noted. Patients who improved in either visual sensitivity or BCVA also anecdotally reported noticeable improvement in visual function, including greater clarity and reduced night blindness. Preliminary data for additional patients enrolled at a new, higher-dose group are consistent with previous data.

Safety data from all 25 patients dosed so far continue to show a favorable profile, with no dose-limiting inflammatory responses observed and no secondary inflammatory responses requiring re-administration of any steroid in any patients. The company said it is scheduling more patient enrollments during the first quarter of this year, with an aim of generating the most robust set of data possible as plans proceed for the pivotal trial.

At the end of the second quarter, the company expects to sit down for an end-of-phase II meeting with regulators. “Endpoints are going to be a big [part of the] discussion with the FDA,” Washer said. Parties will also talk about the size of the next experiment, “and the statistics we're using to determine the number of patients to put in the trial, randomization protocols, [and] support that we have that the product has shown safety, which we really feel we have quite a bit of data on that at this point. And then the dose that we’re going to be using.” In mid-February 2019, AGTC said it had completed enrollment in the two highest-dose groups of the phase I/II bid.

XLRP is an inherited condition caused by mutations in the RPGR gene and causes progressive vision loss in boys and young men. The condition begins with night blindness, followed by progressive constriction of the field of vision. XLRP often results in total blindness and there is no specific treatment.

About a month after the six-month data were disclosed, AGTC priced a public offering of 6.5 million shares at $5 each, for gross proceeds of $32.5 million, granting underwriters a 30-day option to buy as many as 975,000 shares.

Continued interest in XLRP by Cambridge, Mass.-based Biogen Inc. was manifested in the company’s agreement, made public in March 2019, to take over Nightstar Therapeutics plc, of London, in a $25.50 per-share bid that valued the company at $877 million, or $800 million minus transaction expenses and anticipated cash at closing. In December of the previous year, AGTC revealed that Biogen was walking away from their three-year-old, potential $1 billion collaboration and returning full rights to the clinical-stage X-linked retinoschisis (XLRS) and XLRP programs plus discovery efforts in adrenoleukodystrophy and two ophthalmic targets. At the same time, AGTC said it was halting development of rAAV2tYF-CB-hRS1, its AAV-based RS1 gene therapy for XLRS, after top-line interim data from its phase I/II trial showed no sign of clinical activity at six months.

The company’s fortunes have improved since. AGTC yielded what Wainwright analyst Joseph Pantginis called “encouraging” results with a pair of gene therapy candidates in achromatopsia (ACHM), addressing the deficiencies of CNGB3 and CNGA3 genes in ACHM patients. In a report, he cited “positive signs of biological activity,” with “changes in light discomfort observed at three months, and a favorable safety profile maintained at six months.” But six-month efficacy outcomes “appear to be inconsistent among patients beyond light sensitivity, suggesting the need for longer time points in order to clarify whether patients are experiencing true clinical improvements.” He pointed out that the pathogenesis of ACHM seems to mean that “improvements may be observed quickly at a younger age and require treatment for a longer period,” so AGTC is dosing pediatric patients. Enrollment in both studies is expected to complete by the first half of 2020, with interim data from adult patients due in the second half of the year. ACHM is characterized by a partial or total absence of color vision and the ability to see only black, white and shades of gray.

“We love it when a plan comes together,” Pantginis said in his Jan. 29 report. “AGTC has accomplished some major achievements to move beyond a critical, overhanging, show-me-stage.” The firm “is positioning to deliver key catalysts through 2020 and beyond,” in his view.

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