SUBSPECIALTY NEWS

Spark Succeeds in Reversing Blinding Retinal Diseases

First phase 3 study to validate gene therapy

BY JERRY HELZNER, CONTRIBUTING EDITOR

■ Spark Therapeutics (Philadelphia) has announced positive top-line results from the phase 3 pivotal trial of its lead gene therapy product candidate, SPK-RPE65, for the treatment of RPE65-mediated inherited retinal dystrophies (IRDs).

The pivotal trial met its primary endpoint demonstrating improvement of functional vision in the 21-patient intervention group compared to the 10-patient control group, as measured by the change in bilateral mobility testing between baseline and one year. For example, patients who received the new gene were successful in navigating a marked path in dim light, something they could not do at baseline testing. There were no serious adverse events related to SPK-RPE65 or deleterious immune responses observed in the trial.

In addition, subjects who received SPK-RPE65 outperformed control subjects across the first two secondary endpoints: full-field light sensitivity threshold testing and the mobility test change score for the first injected eye. The third secondary endpoint, visual acuity, did not show statistically significant evidence of benefit.

“We saw substantial restoration of vision in patients who were progressing toward complete blindness,” said Albert M. Maguire, MD, principal investigator in the trial and professor of ophthalmology at the Perelman School of Medicine of the University of Pennsylvania. “The majority of the subjects given SPK-RPE65 derived the maximum possible benefit that we could measure on the primary visual function test, and this impressive effect was confirmed by a parallel improvement in retinal sensitivity. If approved, SPK-RPE65 should have a positive, meaningful impact on the lives of patients with this debilitating condition.”

Based on these results, Spark intends to file a Biologics License Application with the FDA in 2016 as the first step in executing its global regulatory and commercialization strategy.

“These results are the culmination of more than a decade of work of many dedicated individuals to correct the underlying cause of RPE65-mediated blindness through the one-time administration of a gene therapy,” said Jean Bennett, MD, PhD, professor of ophthalmology and director of the Center for Advanced Retinal and Ocular Therapeutics at the Perelman School of Medicine of the University of Pennsylvania. “We are excited about the potential impact that the results will have on the treatment of this and other blinding conditions.”

The results represent the first successful randomized, controlled phase 3 trial ever completed in gene therapy for a genetic disease. It reflects more than a decade of innovation across all aspects of the program, including vector design, manufacturing and formulation, the surgical delivery procedure and clinical trial design, as well as the development and validation of a novel endpoint.

“This is an important moment for the field of gene therapy, and demonstrates Spark’s ability to carefully and precisely integrate technologies and approaches across a range of disciplines to move the concept of gene therapy toward a therapeutic reality for patients,” said Kathy High, MD, cofounder, president, and chief scientific officer of Spark. “We wish to thank the trial participants and families as well as the investigators and all who contributed to this ground-breaking trial and successful result.”

New Technology Assesses Photoreceptor Function

VIS-OCT permits monitoring of disease progression.

■ A collaborative Bascom Palmer Eye Institute and Florida International University (FIU) biomedical engineering team has developed a breakthrough retinal imaging technology that could help clinicians diagnose and assess the extent of vision loss in patients with a wide range of conditions.

After three years of work, the Bascom Palmer and FIU researchers successfully tested the first visible-light optical coherence tomography (VIS-OCT) technology for imaging rhodopsin, the light-sensing molecule contained in the retinal photoreceptors that convert light signals to neuronal signals sent to the brain.

Shuliang Jiao, PhD, associate professor, department of biomedical engineering at FIU and Bascom Palmer alumnus, led the project. He designed and built the first VIS-OCT capable of imaging rhodopsin, and is the senior author of an article describing the novel VIS-OCT technology, “Depth-resolved rhodopsin molecular contrast imaging for functional assessment of photoreceptors,” published recently in Scientific Reports. The research was supported by grants from the National Institutes of Health.

“OCT has been used extensively in ophthalmology clinics,” said Dr. Jiao. “Our work shows the new technology can be used to construct an accurate map showing the distribution of rhodopsin — a functional biomarker of the rod photoreceptors in the retina. We now are working on making this imaging equipment more patient-friendly to move it into the clinical setting.”

Dr. Jiao added that the VIS-OCT-created map could help determine the effectiveness of treatments in retinal disorders that affect the photoreceptors. For example, the progressive loss of photoreceptors in patients with hereditary retinal degeneration can be objectively measured and documented for clinical care and evaluation of treatments.

“This technology can be used to monitor disease progression for retinitis pigmentosa, age-related macular degeneration, and other retinal diseases,” said coauthor Byron L. Lam, MD, of Bascom Palmer, a physician-scientist who specializes in photoreceptor degeneration. “It can also be used to objectively measure the outcomes for treatments and clinical trials of new therapies,” he added.

Coauthor Rong Wen, also of Bascom Palmer and a photoreceptor cell biologist, believes VIS-OCT technology will also be useful to study future photoreceptor regeneration, including transplant stem cell-derived photoreceptors, gene therapies, neuroprotection therapies using neurotrophic factors, and other neuroprotective agents.

“The rapid development in regenerative medicine to restore vision has raised a hope that regeneration of photoreceptors and restoration of photoreceptor function will become reality in the near future,” he said. “When the time comes, this technology will be used to see whether the new photoreceptors are functional.”

Ocata Begins Phase 2 Stem Cell Trial

Phase 1 showed efficacy in dry AMD.

■ Ocata Therapeutics (Marlborough, MA), a leader in the field of regenerative ophthalmology through stem cell therapy, said the first patient has been enrolled in the company’s phase 2 clinical trial using Ocata’s proprietary RPE cells in patients with dry AMD. The purpose of the trial is to evaluate safety and explore efficacy as compared to a parallel control group. Interim top-line results from the first cohort is expected in the second quarter of 2016, and the interim readout on the second two cohorts is expected by the end of 2016.

“We expect this phase 2 clinical study will provide important information about the ability of Ocata’s fully differentiated RPE cells to treat dry age-related macular degeneration when transplanted into the retina,” commented Carl D. Regillo, MD, FACS, director, Retina Service at Wills Eye Hospital and professor of ophthalmology, Jefferson Medical College. “We are pleased to be a participating site in this clinical trial, as we believe that Ocata’s RPE program has the potential to be an effective treatment option for dry AMD, as well as other ophthalmological indications, such as Stargardt’s disease.”

This phase 2 study will include up to three cohorts of up to 20 subjects each. Each of the cohorts will receive one week of immune suppressive therapy prior to surgery and then different immune suppression regimens following transplantation of the cells, to determine the safety and tolerability of 0, six, and 12 weeks of post-transplant systemic immune suppression. Untreated patients will receive placebo treatment similar in appearance and administration to those who have received cellular transplants.

“A key goal of this study is to more fully explore the efficacy signal that we reported in the Lancet in October of last year, with comparison to a control group of untreated patients rather than using the fellow eye for comparison. We believe that the data developed in this phase 2 study will allow us to optimize the addressable patient population using well-controlled data while assessing potential endpoints for efficacy,” said Eddy Anglade, MD, chief medical officer of Ocata. “We expect that the data produced by this study will provide valuable guidance for the design of a phase 3 program and could ultimately inform our commercial strategies.”

Iluvien Proves Effective in “Real-world” Study

Significant vision gains; few side effects

■ A paper entitled “Real World Experience of Fluocinolone Acetonide Intravitreal Implant in the Treatment of Diabetic Macular Edema” provides a positive review of 28 cases from six sites in the UK and four sites in Germany, the first two countries in which the Iluvien sustained-release implant was launched by Alimera Sciences Limited. The study was led by Fahd Quhill, MD, consulting ophthalmologist of the Royal Hallamshire Hospital, Sheffield, UK.

The mean follow-up after injection of Iluvien was 13 weeks in these case reports. The average change in the Early Treatment Diabetic Retinopathy Study (ETDRS) letter score from baseline was an increase of 14 letters, with 15 eyes (54%) achieving greater than 10 letters of improvement and nine eyes (32%) achieving greater than 15 letters of improvement. The average decrease in central foveal thickness (CFT) was 167 microns, while in 15 eyes (54%) CFT decreased to below 300 microns.

In these cases, each eye had received prior treatment, with 57% having been treated with corticosteroid, 57% having been treated with laser, and 93% having been treated with anti-VEGF agents. Those eyes receiving prior anti-VEGF treatment received an average of 5.3 injections before Iluvien was administered, reflective of the current clinical practice and standard of care in the UK and Germany.

The use of corticosteroids is associated with accelerated development of cataract and elevated IOP. In these cases, the introduction of IOP-lowering medication was required in two eyes (7%) compared with 38% in the FAME Study, Alimera’s pivotal phase 3 study.

“Real-world data on the use of Iluvien in the UK and Germany, as collected in this series of cases, have shown efficacy equivalent to that seen in the FAME Study,” said Dr. Quhill. “In the limited number of cases reported in the public domain, the number of patients experiencing an elevation in IOP are fewer than reported in the FAME Study.”

Sirolimus Trial for Uveitis Shows Promising Results

Data from EURETINA in France

BY LAIRD HARRISON

■ In Intravitreal sirolimus significantly reduced inflammation while preserving vision in patients with noninfectious posterior uveitis, a researcher says.

“I think this is of interest to retina specialists,” Phuc Le Hoang, MD, PhD, told Retinal Physician. “You can handle cases without the help of an internist, without the help of a uveitis specialist.”

Dr. Le Hoang, professor and chair of ophthalmology at the Pitié Salpêtrière Hospital at Pierre and Marie Curie University in Paris, France, presented the findings of the multinational SAKURA Study 1 at the European Society of Retina Specialists 15th EURETINA Congress in Nice, France.

Noninfectious uveitis of the posterior segment is typically chronic and requires long-term treatment to prevent structural damage and vision loss, he said.

Current treatments include corticosteroids and immunomodulators. They are only partially effective and may cause adverse effects, Dr. Le Hoang said Sirolimus offers the advantage that it can be administered with a local injection.

An immunosuppressant used in kidney transplants, sirolimus inhibits mammalian target of rapamycin (mTOR).

“It inhibits not only the T-cell proliferation driven by IL-2 or other pro-inflammatory cytokines but also B cells,” said Dr. Le Hoang. “And we know that in uveitis, T and B cells might be involved.”

To test safety and effectiveness of sirolimus for uveitis, Dr. Le Hoang and his colleagues recruited 347 patients with the condition from 103 sites in the United States, India, Europe, Latin America, and Japan. The patients had a mean age of 47 and had been diagnosed for a median of 26 months. The patients started with a mean best corrected visual acuity of 65.3 letters.

The patients discontinued immunomodulatory therapy 30 days prior to starting sirolimus and tapered their topical corticosteroids to discontinue by the first day of the trial.

Patients on systemic corticosteroids were allowed to continue through the first day, but then began rapid tapering.

The patients were randomly divided in thirds. Each group received a different dose of sirolimus: 44 µg (considered an active control), 440 µg, or 880 µg in injections every two months. They remained blind as to the dose they were receiving until week 6, when they all switched to open label injections of 880 µg every two months through month 12. From month 12 to month 24, they continued receiving injections as needed.

At month 5, 22.8% of the patients receiving the 440-µg dose achieved the primary endpoint: vitreal haze of 0. By comparison, 10.3% of the patients on the 44-µg dose and 16.4% of the patients on the 880-µg dose achieved this endpoint. The difference between the 440-µg dose patients and the other two groups was statistically significant (P=.025).

In response to a question from the audience, Dr. Le Hoang theorized that the 880-µg dose may suppress beneficial T cells, as well as those involved in the uveitis. “It was shown in our animal models that high dosage may be toxic to the retina,” he said.

When the investigators added to these patients the number who had vitreal haze of 5+ at month 5, the percentages grew to 52.6% for the 440-µg dose, 43.1% for the 880-µg dose, and 35% for the 440-µg dose. In this analysis, the difference between the 440-µg dose and the others was even more significant (P=.008).

Changes in vitreal haze scores followed similar trend lines for all three groups, dropping most sharply in the first month and more gradually after that. The mean change in the 440-µg group was -1.05 at month 6.

The mean change in ETDRS letters was greatest in the patients who started out with visual acuity worse than 20/100. The patients with this visual acuity taking 440 µg gained 10.5 ETDRS letters. For other doses and better visual acuity, changes in ETDRS letters ranged from 1.0 to 5.5 letters.

The difference between doses was less striking when the investigators compared the patients’ success in tapering off their use of systemic corticosteroids.

Of the 22 patients taking the 44-µg dose who were on systemic corticosteroids, 63.6% completely discontinued them. Among the 26 patients on the 440-µg dose, the proportion was 73.1%, and among the 21 patients in the 880-µg group, it was 66.7%.

The patients did not escape serious adverse events, but the percentage suffering from them was similar in the three groups at month 12: 23.1% for 44 µg, 24.1% for 440 µg, and 20.5% for 880 µg.

“We had a lot of flare-up of inflammation,” said Dr. Le Hoang. “It is due, of course, to discontinuation of topical steroids of IMTs and of systemic steroids.”

Intraocular pressure remained steady from baseline, however.

“We can conclude that intravitreal sirolimus can induce an improvement in intraocular inflammation in noninfectious uveitis of the posterior segment with the preservation of the vision,” Dr. Le Hoang concluded.

“It is maintained all along, even along the open-label period. And we think that it can be a good adjunct treatment for long-term corticosteroid sparing.” RP