David Hutton

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Imaging before treatment (left column) and repeated imaging again after two months of hydroxyurea treatment (right column). Before treatment, the patient exhibited between-session IPI of 3.0% and 2.7% respectively at the parafovea (A) and temporal retina (C). After two months of hydroxyurea, the between-session IPI was reduced to 0.5% and 1.6% respectively at the parafovea (B) and temporal retina (D). (Images courtesy of New York Eye and Ear Infirmary of Mount Sinai)

Ophthalmologists at New York Eye and Ear Infirmary of Mount Sinai have created a new technique to evaluate patients with sickle cell retinopathy and assess the disease before it progresses and leads to permanent vision loss.

Using optical coherence tomography (OCT) angiography--an advanced imaging system that captures the motion of red blood cells in blood vessels non-invasively--the researchers discovered that sequential imaging of affected retinal blood flow in sickle cell patients can help assess how the disease is progressing and how effective their treatment is for reducing focal vascular strokes.

According to lead investigator Toco Chui, PhD, director of the Marrus Adaptive Optics Laboratory at New York Eye and Ear Infirmary of Mount Sinai, investigators added a new dimension to ocular imaging technology that no one had thought of before.

“For the first time, we have shown that by doing rapid, repeated retinal imaging of sickle cell patients, you can see microscopic changes in blood vessels and blood flow,” Chui said in a statement. “The more the blood flow fluctuates across images, the more at risk patients are for a permanent blockage, which severely damage their eyesight."

Chui also pointed out that using the approach, investigators can non-invasively monitor the retina over time and see how a patient is doing before or after initiation of therapy.

Sickle cell disease is an inherited red blood cell disorder caused by a mutation in hemoglobin. The hemoglobin folds abnormally and distorts red blood cells into a sickle shape; the sickle-shaped cells clump together and can block blood flow. 

This causes repeated damage to capillaries, which become inflamed and sticky, resulting in permanent blockages that can affect vision in the retina, and in some cases, major bleeding and retinal detachment.

According to co-author Richard Rosen, MD, Belinda Bingham Pierce and Gerald G. Pierce, MD Distinguished Chair of Ophthalmology, and chief of Retina Services for the Mount Sinai Health System, investigators’ work can be a game-changer for sickle cell patients, especially for those who have no symptoms of retinopathy.

“It can lead to earlier diagnosis of retinal issues and prevention of irreversible blindness,” he said. “Without this technology, it is impossible to judge their eye condition until patients report vision loss, when it's too late."

Investigators analyzed 27 participants. Thirteen had sickle cell disease with retinopathy of varying severity levels. Some were on standard therapy (hydroxyurea) and others were not on treatment. The remaining 14 were controls, with no sickle cell disease or retinopathy.

According to investigators, the team used OCT angiography to image all subjects 10 times in a row over a 10-minute span. An hour later they repeated the imaging procedure. 

They analyzed the blood vessels that repeatedly opened and closed—a trait of sickle cell disease. When this happens, blood cannot flow freely and these blood vessels are at risk of permanent closure which can lead to blindness. 

For patients without sickle cell disease, scans showed that the blood vessels for the most part remained open, providing continuous blood flow.

Moreover, for each patient, the investigators stacked their groups of ten scans together and counted the blood vessels that "flickered." Healthy blood vessels remain white on all scans with no flickering, indicating consistent blood flow in the vessels.

On all scans, the untreated sickle cell patients had substantially more flickering (more intermittent blood flow) than patients on treatment, indicating that treatment was effective. 

Patients with no sickle cell disease had no or very minimal blood flow fluctuations. 

Investigators used measurements of flicker frequency and locations of flickering to develop a computer algorithm for assessing risk of retinal blood blockages in sickle cell patients.

Jeffery Glassberg, MD, director of Mount Sinai's Comprehensive Sickle Cell Program, for the first time ever in sickle cell disease, there are too many good drugs and too little information on who should be on what, and what combinations work best.

“What we hope is that OCT angiography and this new algorithm can be used to solve this problem. Instead of following lab tests and waiting for horrible things to happen to the patient, for the first time we can use this technology to measure the number of vaso-occlusive events that are occurring on a new treatment regimen to find out if it is best for the patient," Glassberg said in a statement.

Davis B. Zhou, a medical student from the Icahn School of Medicine at Mount Sinai, played a key role in creating the algorithm for the study during his extended research elective in the Einhorn Center for Clinical Research at the New York Eye and Ear Infirmary of Mount Sinai.

“Quantification of intermittent retinal capillary perfusion in sickle cell disease

” Davis B. Zhou, Maria V. Castanos, Alexander Pinhas, Peter Gillette, Justin V. Migacz, Richard B. Rosen, Jeffrey Glassberg, and Toco Y. P. Chui, 

Articles

Investigators develop technique to assess progression of sickle cell retinopathy

Biogen Inc. on Friday announced topline results from the Phase 2/3 XIRIUS study of cotoretigene toliparvovec (BIIB112), a gene therapy being investigated as a one-time therapy for patients with X-linked retinitis pigmentosa (XLRP).

Patients living with XLRP currently have no approved treatments. The company noted that the XIRIUS study did not meet its primary endpoint of demonstrating a 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.

This assessment was performed at 12 months and compared to the study eye of patients randomized to the untreated control group. Positive trends were observed across several clinically relevant prespecified secondary endpoints.

Cotoretigene toliparvovec (BIIB112) is an investigational AAV8 vector-based gene therapy administered by subretinal injection, designed to provide full-length functioning retinitis pigmentosa GTPase regulator (

) protein in patients with X-linked retinitis pigmentosa (XLRP) caused by mutations in the 

By replacing the gene, cotoretigene toliparvovec leads to increased levels of the RPGR protein which may potentially slow, stop or prevent further degeneration of photoreceptors in patients with 

Katherine Dawson, MD, head of the therapeutics development unit at Biogen, noted that while the Phase 2/3 XIRIUS study of cotoretigene toliparvovec did not meet its primary endpoint, the company is encouraged by positive trends in other pre-specified clinically relevant endpoints, such as a measure of visual acuity under low light conditions.

“XLRP is a serious, early-onset form of retinitis pigmentosa, and people living with it face almost certain blindness by the end of the fourth decade, commonly leading to loss of independence, depression and unemployment,” she said. “We are working to further evaluate the data from the XIRIUS study before communicating potential next steps for the cotoretigene toliparvovec clinical development program.”

According to the company, most of the adverse events were ocular in nature, mild-to-moderate in severity, and resolved.

Complete analysis of the XIRIUS study is ongoing, and detailed results will be shared in a future scientific forum.

Biogen is advancing its multi-franchise portfolio strategy by pursuing modalities including gene therapy to address significant unmet medical needs. In ophthalmology, in addition to cotoretigene toliparvovec, the company is currently evaluating the safety and efficacy of timrepigene emparvovec (BIIB111/AAV2-REP1), a gene therapy being investigated for the one-time treatment of choroideremia, a rare inherited retinal disease.

The company also announced a global collaboration and licensing agreement with ViGeneron GmbH to develop and commercialize gene therapy products based on adeno-associated virus (AAV) vectors with the aim of treating inherited eye diseases as well as a licensing agreement with Massachusetts Eye and Ear to develop a gene therapy for the potential treatment of inherited retinal degeneration due to mutations in the 

 gene. In addition to Biogen’s gene therapy candidates for various ophthalmic conditions, the company also entered into an agreement with Catalyst Biosciences to develop and commercialize pegylated CB 2782 for the potential treatment of geographic atrophy, an advanced form of dry age-related macular degeneration that leads to blindness that has no approved therapies.

XIRIUS was a first-in-human, multicenter, randomly assigned, three-arm dose-escalation and dose-expansion study of a single subretinal injection of cotoretigene toliparvovec in males with a genetically confirmed diagnosis of X-linked retinitis pigmentosa. Part I was a 24-month dose-escalation study (n = 18, ≥ 18 years of age); Part II was a 12-month dose expansion study (n = 32 randomized ≥ 10 years of age), with a high dose and low dose selected from Part I based on a benefit/risk assessment and a third untreated group to allow for a controlled comparison of efficacy and safety. At study completion, treated subjects in Parts I and II have been invited to participate in a separate long-term follow-up study that will collect efficacy and safety data up to five years from treatment.

While Biogen’s XIRIUS study did not meet its primary endpoint of demonstrating a statistically significant improvement in treated eyes, positive trends were observed across several clinically relevant prespecified secondary endpoints.

Results unveiled from phase 2/3 gene therapy study for XLRP

A minimally invasive retinal reattachment procedure, which can be performed in an ophthalmologist’s office, may offer improved long-term integrity and structure of the retina's photoreceptors compared with more invasive operating room procedures, according to new research.

The study was led by investigators at St. Michael's Hospital of Unity Health Toronto, contributes to a growing body of evidence pointing towards pneumatic retinopexy (PnR) as the better first-line retinal reattachment technique to achieve the best visual outcomes.

According to investigators, retinal detachment is the most common surgical ocular emergency, progressing to loss of vision within hours or days. While there are a number of different treatment options, there is limited high-quality data guiding the choice of surgery.

"Our study shows there is a difference in the long-term integrity of the photoreceptors between different surgical techniques, and these anatomic differences were associated with visual outcomes," co-principal investigator Rajeev H. Muni, MD, a vitreoretinal surgeon at St. Michael’s and researcher at the Li Ka Shing Knowledge Institute, said in a statement.

During previous studies carried out at St. Michael’s Hospital, patients had better visual results following the less invasive PnR compared to pars plana vitrectomy (PPV). In the study, the investigators determined there was an actual difference in photoreceptor anatomic recovery between the two retinal reattachment techniques.

Using data from a randomly assigned trial conducted at St. Michael’s Hospital, investigators compared the retinal scans of 72 patients who had retinal reattachment using PPV and 73 patients who had retinal reattachment using the minimally invasive PnR at 12 months post-operatively.

According to investigators, PnR offers ophthalmologists a less invasive and less expensive retinal reattachment technique that can be done in the office. In PnR, a small gas bubble is used to close the retinal tear and allow the fluid to reabsorb naturally and slowly. PPV is a surgical technique where the fluid under the retina is rapidly aspirated and removed, forcefully bringing the retina back in position.

Investigators found that the imaging showed that discontinuity was more common at 12 months post-operatively among patients who had the PPV surgical reattachment than in patients who had the minimally invasive PnR procedure. The discontinuity indicates damage to cells that are critical for vision and this damage was found to be associated with worse visual outcomes.

“This data provides an objectively determined anatomic basis for the superior functional outcomes seen with pneumatic retinopexy that we have previously reported," according to Roxane J. Hillier, MD, the trial's other co-principal investigator who is now based in the United Kingdom.

The researchers say their findings highlight that closing the retinal tear, doing as little else as possible, and allowing the retina to reattach naturally leads to the best outcomes both from an anatomic and visual perspective.

"This was previously unknown, and in my opinion will be a game-changer in our field," Dr. Muni concluded.

1 Rajeev H. Muni, MD; Tina Felfeli, MD; Srinivas R. Sada, MD; et al; Postoperative Photoreceptor Integrity Following Pneumatic Retinopathy vs Pars Plana Vitrectomy for Retinal Detachment Repair; 

 Published online April 22, 2021. doi:10.1001/jamaophthalmol.2021.0803

A study led by investigators at St. Michael's Hospital of Unity Health Toronto supports pneumatic retinopexy as a primary retinal reattachment technique to achieve better long-term integrity of photoreceptors.  

Minimally invasive retinal reattachment procedure leads to enhanced photoreceptor integrity

Ocuphire Pharma Inc. announced today that it has completed enrollment in the VEGA-1 Phase 2 clinical trial (

) evaluating the safety and efficacy of a combination kit of 0.75% phentolamine (Nyxol) and low-dose pilocarpine in presbyopia.

According to the company, VEGA-1 successfully recruited 150 subjects in just under 3 months.

According to Mina Sooch, MBA, president and CEO of Ocuphire Pharma, hitting the enrollment completion target for the VEGA-1 trial is another milestone in the company’s Nyxol program and tracks for top-line results by the end of June.

“Nyxol has the potential to address multiple unmet needs initially with the large market opportunity in reversal of mydriasis supported by our recent positive Phase 3 data results and then adding this very large presbyopia market opportunity that is estimated at over $5 billion in the US alone,” Sooch said in a statement. “We are excited to develop Nyxol with low-dose pilocarpine as a potential option for the growing number of presbyopic patients and to also realize commercial synergies if products are approved given the common targeted optometrists and ophthalmologists.”

Ocuphire noted that the global prevalence of presbyopia is estimated to be 2 billion. 

An estimated 120 million Americans live with presbyopia, a large prevalence that is expected to exceed 150 million by 2034. There are currently no approved drug therapies for presbyopia.

Moreover, when it comes to payment, presbyopia corrective devices generally have been mostly out-of-pocket cash pay by patients

Marguerite McDonald, MD, FACS, a clinical professor of ophthalmology at the NYU Langone Medical Center and an Ocuphire Medical Advisory Board member, pointed out that presbyopia is a condition that affects nearly everyone over the age of 40.

“Many patients reliant on reading glasses and contact lenses desire more flexibility and convenience and continually request alternatives or a complementary choice,” she said in a statement. “Development of eyedrop treatments for Presbyopia has recently become very active, led by Allergan having recently submitted an NDA for this indication.”

McDonald noted that there is room for many options given the large unmet need, and she said she is encouraged by Nyxol eye drops in combination with low-dose pilocarpine eye drops as a differentiated solution that works both on the iris dilator and sphincter muscles.

“This combination product should allow for moderate unopposed pupil constriction and provide the ability to see both at near and at distance without the side-effects such as brow ache, headache, blurry vision, and loss of distance night vision associated with the use of higher doses of pilocarpine,” she said.

According to a GlobalData market research report, 69% of patients would consider an eye drop as an alternative to reading glasses. 

More than 70% of patients indicated that they wear reading glasses in the morning, afternoon, and evening, suggesting that patients desire a solution with durability. 

More than 50% of responders also indicated that using drops 2 to 4 times per day would be moderately to very convenient to them. 

In addition, 66% of surveyed eyecare providers indicated interest in a Nyxol and low-dose pilocarpine product profile as a potential therapeutic alternative to reading glasses.


The VEGA-1 clinical trial is designed to evaluate the efficacy and safety of Nyxol in combination with low-dose pilocarpine compared to placebo in presbyopic subjects. A total of 150 subjects have been enrolled at 17 investigational sites in the US from mid-February to mid-May of this year.

The Phase 2 trial is randomly assigned, double-masked, placebo-controlled with 4 treatment arms. 

At the first visit, subjects are randomized to receive either Nyxol or placebo drops that are instilled at home near bedtime for 3 to 4 days prior to Visit 2; at Visit 2 subjects then receive either low-dose pilocarpine or no treatment with efficacy and safety measurements collected at multiple timepoints through 6 hours.

The primary endpoint is the percentage of subjects with ≥ 15 letters of improvement in photopic binocular near vision (i.e. distance-corrected near visually acuity, DCNVA) at 1 hour on Visit 2 for Nyxol + low-dose pilocarpine arm compared to placebo alone arm. 

Secondary endpoints at multiple timepoints include improvements of 3 lines of DCNVA without any loss of distance vision, pupil diameter, and improvements of DCNVA at 1 and 2 lines compared to placebo as well as to each Nyxol and low-dose pilocarpine alone.

Top-line results are expected by the end of Q2 2021.

Ocuphire collaborated closely with Oculos Development Services, a Tampa, Florida based clinical research organization and a subsidiary of Iuvo BioScience, on the launch and execution of the VEGA-1 trial.

“We are pleased by the rapid enrollment in this Phase 2 trial, which speaks to the unmet need of an eye drop to benefit vision correction for patients with presbyopia,” Chuck Slonim, MD, chief medical officer and medical monitor of Oculos Development Services, said in a statement. “We thank our investigators, clinical coordinators, staff, and subjects for their support and ease of trial execution at 17 sites across the US.”

Ocuphire Pharma has completed enrollment in the VEGA-1 Phase 2 clinical trial evaluating the safety and efficacy of drops to treat presbyopia. 

David Hutton

Articles

Results unveiled from phase 2/3 gene therapy study for XLRP

Minimally invasive retinal reattachment procedure leads to enhanced photoreceptor integrity

Enrollment completed in VEGA-1 Phase 2 clinical trial for presbyopia treatment

Investigators develop technique to assess progression of sickle cell retinopathy