Nightstar Therapeutics plc opened the phase III registration trial of lead candidate NSR-REP1 to evaluate the gene therapy in individuals with the rare degenerative, X-linked disorder choroideremia (CHM), which presents in childhood as night blindness and ultimately leads to complete blindness. The STAR trial is expected to enroll approximately 140 participants across 18 sites, including six surgical centers, in the U.S., Europe, Canada and South America. The primary endpoint is the proportion of patients in the high-dose treatment arm compared with control who demonstrate visual acuity improvement of at least 15 ETDRS letters 12 months following treatment, compared to baseline.

In data from 32 patients treated with NSR-REP1 across four investigator-sponsored open-label phase I/II trials, more than 90 percent maintained or improved their visual acuity over a one-year follow-up period.

London-based Nightstar relied heavily on the data from those four centers to inform the design of the pivotal trial, according to CEO Dave Fellows.

"And, of course, we had the feedback from each of those surgical investigator sites to guide us on patient selection and the endpoint we adopted for the phase III trial," Fellows told BioWorld.

Patients enrolled in STAR will be randomized into one of three study arms, with 56 receiving a high dose of NSR-REP1 in one-eye (1 × 10^11 genome particles, or gp); 28 receiving a low dose of NSR-REP1 in one-eye (1 × 10^10 gp); and 56 patients receiving no treatment (no-sham, parallel control arm).

Participants in STAR – the first phase III in CHM – are expected to be recruited almost exclusively from the ongoing Nightstar-sponsored NIGHT natural history observational study, which has enrolled approximately 240 CHM patients over the past two years.

"We're fortunate already to have our pool of patients identified from which to move forward into the phase III trial," Fellows said. "We have a fair amount of baseline data on those patients, which is another extremely valuable input."

NSR-REP1 comprises an adeno-associated virus, or AAV2, vector containing recombinant human complementary DNA (cDNA) designed to produce REP1 inside the eye. NSR-REP1 is administered surgically by injection into the subretinal space following a standard procedure in which some of the vitreous – the clear gel that fills the space between the lens and retina of the eye – is removed to allow better visualization of the injection site.

The introduction of a functional CHM gene into patients is intended to allow expression of REP1, thus slowing or stopping the progression of CHM and corresponding decline in vision.

Nightstar reached concurrence with the FDA and EMA on the trial design, and a number of sites are located in Europe. Still, Fellows was cautious on setting expectations about a timetable for the study.

"The honest answer is we don't know" how long the study will take to recruit, he said, citing logistical factors such as patient travel to surgical centers and coordinated booking of the surgical suites. During its IPO process last year, Nightstar guided a recruitment time frame of 12 to 15 months for the pivotal study to enroll fully. Top-line data are expected about a year after that.

Nightstar isn't spun up about exact dates, however. The company has sufficient cash – $69.6 million as of June 30, 2017, plus $76.9 raised in its October 2017 IPO – to complete the phase III CHM study and an ongoing phase I/II study of follow-on candidate NSR-RPGR in X-linked retinitis pigmentosa (XLRP), which is characterized by mutations in the RPGR gene that lead to a lack of protein transport and a loss of photoreceptors, resulting in rapid disease progression and severe retinal dysfunction.

NSR-RPGR consists of a standard AAV vector that includes codon-optimized human RPGR DNA that features higher protein expression levels than a wild-type RPGR coding sequence and greater sequence stability. NSR-RPGR is designed to produce RPGR-ORF15, the form of RPGR preferentially expressed in the retina.

Safety data from at least a subset of patients in the dose-ranging study are expected in the second half of the year. Nightstar also plans to initiate a prospective natural history observational study in XLRP across multiple clinical sites.

Focus on 'more prevalent' of rare retinal diseases

Nightstar isn't the first to apply gene therapy to vision diseases. Spark Therapeutics Inc. already gained FDA approval for the gene therapy Luxturna (voretigene neparvovec-rzyl) to treat RPE65 mutation-associated retinal dystrophy, and nearly 200 gene therapy approaches – half of them still in discovery – are targeting ocular indications, from various forms of macular degeneration to retinopathies, glaucoma and Stargardt disease, according to Cortellis Competitive Intelligence. (See BioWorld, Dec. 20, 2017.)

Nightstar's differentiated approach is to focus exclusively on rare inherited retinal diseases – in particular, "the more prevalent of the rare diseases in that space," where the company has built a network of strong partnerships with retinal disease centers and surgeons, Fellows said.

In addition to its clinical candidates, Nightstar has two of the early stage assets: NSR-BEST1, composed of a standard AAV vector combined with the human BEST1 cDNA and a WPRE sequence, to treat Best vitelliform macular dystrophy, and NSR-ABCA4 targeting Stargardt.

Provided the STAR trial succeeds, Nightstar plans to piggyback on its strengths in the retinal disease field to take the CHM program to market on its own.

"This is a center of excellence strategy," Fellows said, noting that initial surgery can be performed in only 20 to 25 centers. "We think that's very doable through our own commercial structure." Although the company is listening to inbound interest from players in various regions, "we're moving ahead, at least in the U.S. and Europe, to build our own commercial structure," he added.

The "STARs are aligned for NITE," Leerink Partners LLC Joseph Schwartz headlined his flash note.

"Despite a potential competition from Spark's SPK-CHM, a positive outcome from the phase III NITE study could position Nightstar favorably in this rare indication, and we project peak sales [opportunity] of ~$830 million (2026E)," he wrote.

"Across multiple studies, NSR-REP1 either maintained or improved visual acuity (VA) with durable effects," Schwartz added. "Benefiting from the lessons learned (e.g., surviving retinal epithelial cells at baseline) as well as the fact that blindness is a long-term progression, Nightstar has designated hyper-responders as the primary endpoint of the STAR study. Defined as an improvement of at least 15 ETDRS letters from baseline in VA at 12 mos. post-treatment, phase III STAR is 90 percent powered to detect ≥20 percent treatment benefit. If so, there are precedents for such a magnitude receiving regulatory approval in the ophthalmic disease space."

"We believe Nightstar Therapeutics is leading the way in gene therapy for the treatment of choroideremia," Mizuho Securities USA analyst Difei Yang wrote last week in a note initiating coverage of the company. "Given very encouraging results in phase I/II trials, we see strong potential for NSR-REP1 with additional upside from the company's earlier-stage pipeline products."

Nightstar's shares (NASDAQ:NITE) closed Monday at $14.01 for a gain of 91 cents, or 7 percent.