SUBSPECIALTY NEWS

Final Report on 2011 Endophthalmitis Outbreak

A range of outcomes in 25 injected eyes

BY JERRY HELZNER, CONTRIBUTING EDITOR

■ It was national news in 2011 when 25 eyes in California and New York were injected with tainted triamcinolone obtained from a Florida compounding pharmacy that has since been closed. This incident resulted in 22 cases of fungal endophthalmitis traced to the organism Bipolaris hawaiienis. Researchers led by Kent W. Small, MD, and Fadi Shaya, research coordinator, both from the Macula and Retina Institute, Glendale, CA, set out to determine the four-year, final outcome of each of the cases.

What the researchers found was a wide range of final outcomes. Three of the injected eyes never showed signs of infection, possibly because of variations in the fungal load present in the triamcinolone. Five eyes had to be enucleated because the fungal organism persisted despite aggressive local and systemic therapy over a period of a year. Eight eyes had 20/50 or better vision at the four-year mark; three had count fingers, and six had light perception or no light perception.

Treatments included high-dose oral voriconazole, amphoptericin B plus voriconazole, and frequent pars plana vitrectomy. Of these, the best outcomes were achieved with high-dose voriconazole (300 mg PO BID). The researchers found that diagnostic techniques such as fungal cultures were extremely insensitive and polymerase chain reaction (PCR) was totally worthless. Vitreous tap also was inadequate. Direct vitreous biopsy by PPV with cytospin was only 50% sensitive.

“Patients who were placed on the antifungal oral voriconazole had a better chance of showing minor improvement over the course of their treatment,” said Mr. Shaya. “This was the therapy that produced the best results.”

A complete report on this research was presented at the 2016 ARVO meeting in Seattle.

Editas Selects Eye Disease for Gene Editing

Fixing a defective part of an LCA gene

■ Over the last several years, we have heard a great deal about gene replacement therapy as a method to treat a range of retinal diseases. With gene therapy, a healthy gene is delivered via an adeno-associated virus (AAV) vector to take the place of the defective gene. Results thus far for gene therapy in retinal diseases have ranged from highly promising to disappointing, with a number of trials now under way by companies such as Spark Therapeutics (Philadelphia) and AGTC (Alachua, FL).

Now, however, companies such as Editas and Intellia (both Cambridge, MA) have come forward with a newer concept called gene editing, by which only the defective area of a gene is replaced through what is essentially a “cut-and-paste” process. Intellia has new financial commitments from Regeneron and Novartis, though few specifics have been announced as yet. Meanwhile, Editas recently announced that it will initiate its first human trial in 2017, in which it will replace the defective part of the mutated CEP290 gene in patients with a specific form of Leber congenital amaurosis (LCA). Of a total of approximately 3,000 LCA patients in the United States, only about 600 have this form of the disease.

Editas has selected this form of LCA for its first human study because the CEP290 gene is too large for an entire gene to be delivered via an AAV vector. As explained by the Foundation Fighting Blindness, which supports novel approaches to combating retinal disease, Editas uses the cut-and-paste technology known as CRISPR/Cas9 to correct defective copies of CEP290. (The CRISPR acronym stands for: Clustered, Regularly Interspaced Short Palindromic Repeats/CRISPR-associated protein 9.) CRISPR, which comes from the immune system in strep bacteria, locates the region in the gene that needs correction. Cas9 is the molecular scissors that cuts out the mutation.

“While gene-editing systems like CRISPR/Cas9 are not as developed as gene-replacement technologies, we are excited about their potential,” says Stephen Rose, PhD, chief research officer of the Foundation Fighting Blindness. “In addressing the diverse and complicated world of inherited retinal diseases, we definitely need multiple tools in our tool belt.”

Editas is now a publicly traded stock after selling approximately 6 million common shares at $16 a share in early February of this year. Editas trades under the stock symbol EDIT and the CEO is Katrine Bosley, who joined Editas in 2014 after serving as CEO of Celgene Avilomics Research. Intellia has also indicated an interest in going public in the near future.

Vit-Buckle Society Holds Annual Meeting

Live surgery session highlights conference.

■ The Vit-Buckle Society (VBS) held its fourth annual meeting in Miami Beach in mid-March, an event that continues to grow. This year’s meeting was attended by 165 ophthalmologists. The organization, which was formed in 2006 by five vitreoretinal fellows at the annual Fellows Forum in Chicago, mentors developing vitreoretinal surgeons, nurtures innovative surgical technologies and therapeutic approaches to retinal disease, and fosters best practices.

One of the highlights of this year’s meeting was a live surgery session, reports Thomas Albini, MD, VBS president. “We had four surgeons (Daniel Miller, MD, PhD, Cincinnati, on the Synergetics/Valeant Versavit 2.0 platform; J. Michael Jumper, MD, San Francisco, performed his surgical case with Dutch Ophthalmic EVA; Suber Huang, MD, MBA, Cleveland, used the Bausch + Lomb, Stellaris PC; and Maria Berrocal, MD, San Juan, Puerto Rico, operated with the Alcon Constellation) operating in their own surgical centers on four different vitrectomy machines with live two-way audio–visual feeds to the meeting room. Ross Lakhanpal and Derek Kunimoto led the session with the help of Tim Murray, Dean Elliott, and Caroline Baumal, who did a superb job moderating. The session exceeded all our expectations. We are likely to repeat the live surgery demonstration at the meeting next year and we already have some ideas about what our new thing will be for next year at Caesar’s Palace in Las Vegas on April 6-8, 2017.”

Steve Charles, MD, noted innovator of tools and techniques for vitreoretinal surgery, was the keynote speaker for the meeting and Tim Murray, MD, of Miami, received the Mentorship Award for his dedication to supporting VBS through its first decade.

John Kitchens, MD (left), interviews Steve Charles, MD, at the Vit-Buckle Society annual meeting. Dr. Charles spoke to the group about his motivation and accomplishments as an innovator in vitreoretinal surgery.

Ohr Starts Phase 3 Study of AMD Eyedrop

FDA agrees to endorse trial design.

■ Ohr Pharmaceutical, Inc. (New York, NY), a clinical-stage biotechnology company developing a topical eyedrop therapy for retinal disease, has reached an agreement on a Special Protocol Assessment (SPA) with the FDA on the design of the phase 3 trial for its lead drug candidate, squalamine lactate ophthalmic solution, 0.2%. Based on the SPA, Ohr has initiated the first of two planned phase 3 global clinical studies evaluating the efficacy and safety of squalamine, given in combination with Lucentis (ranibiz-umab, Genentech), for the treatment of wet AMD.

“We are extremely pleased to have completed the SPA process. This agreement with the FDA enables us to move forward with the squalamine phase 3 clinical program,” said Jason Slakter, MD, CEO of Ohr. “The initiation of our phase 3 clinical program is a monumental achievement for the company and represents an important step in our mission to develop and commercialize therapeutics for unmet medical needs in ophthalmology.”

“This is fantastic news for the retinal community and the patients in our care,” said Dr. David S. Boyer, retina specialist at Retina-Vitreous Associates Medical Group, Beverly Hills, CA, and a member of Ohr’s Scientific Advisory Board. “Based on my clinical experience, squalamine is a promising drug with the potential to noninvasively improve visual function over the current standard of care. I look forward to the opportunity to enroll patients in this important clinical study.”

The first of two randomized, double-masked, placebo-controlled trials will include approximately 165 centers in the United States and Canada and is expected to enroll approximately 650 treatment-naïve subjects with wet AMD. The primary efficacy endpoint of the clinical trial is the change in visual function at nine months.

Special Protocol Assessment: A Special Protocol Assessment (SPA) from the FDA is a special procedure by which the FDA provides official evaluation and written agreement that the design and planned analysis of a study adequately address the objectives necessary to support a regulatory submission.

RetroSense Studies New Therapy for RP

First patient is dosed in test of optogenetics.

■ RetroSense Therapeutics (Ann Arbor, MI), a privately held biopharmaceutical company, said the first patient has been successfully dosed in an initial phase 1/2a clinical trial to evaluate the safety of RST-001 as a treatment for retinitis pigmentosa (RP). RST-001 uses a process called optogenetics to restore some vision in RP by creating light sensitivity in cells that were previously not light sensitive.

“Successfully dosing our first patient with RST-001 represents a significant milestone in the development program,” said Sean Ainsworth, CEO of RetroSense Therapeutics. “Treating the first human patients should provide key insights into the potential for optogenetics in vision restoration, and beyond. We hope to establish the power of using a gene therapy application of optogenetics to improve vision in individuals with currently incurable blindness.”

David G. Birch, PhD, chief scientist and executive officer of the Retina Foundation of the Southwest and the principal study investigator, added, “Patients enrolling in the trial understand that we are exploring brand new territory but are excited about the possibility of restoring some vision.”

The initiation of this clinical study results from the culmination of several years of research and collaboration with researchers at leading institutions including Zhuo-Hua Pan, PhD, at the Ligon Center in Wayne State University’s Kresge Eye Institute and Richard Masland, PhD, at Massachusetts Eye and Ear Infirmary, early pioneers in optogenetics for vision restoration.

The study is composed of two parts. An initial dose-ranging study is proposed whereby three dose levels of RST-001 will be studied in three separate groups of adult patients with advanced disease. This first part of the study is aimed at determining a single dose of the experimental agent that is safe and well tolerated, to further evaluate in a fourth group of patients. The second part of the study is aimed at obtaining additional safety data at the highest tolerated dose and providing important additional clinical data to guide the design of future efficacy studies.

RetroSense Therapeutics is developing RST-001 as a first-in-class gene therapy application of optogenetics. By applying optogenetics to retinas in which the rod and cone photoreceptors have degenerated, RetroSense is working to confer new light sensitivity to the retina, with the expectation of some degree of improved or restored vision for affected patients.

In 2014, the FDA granted an Orphan Drug designation for RST-001, based on its development as a treatment for RP, a rare disease that affects an estimated 100,000 people in the United States. As a designated Orphan Drug, RST-001 is eligible for various development incentives under the Orphan Drug Act, including a potential waiver from the FDA’s application user fees, certain tax incentives, and Orphan Drug exclusivity. RP