Low-grade inflammation seems to be associated with baseline disease in inherited retinal dystrophies (IRDs), according to Christine N. Kay, MD, a surgeon at Vitreoretinal Associates, in Gainesville, Florida.

Examples of XX include zonular instability in cataract surgeries resulting in intraocular lens dislocations in retinitis pigmentosa (RP), presence of anterior vitreous cells, cystoid macular edema in RP, and retinal antibodies in serum samples from patients with RP. A murine study found that inflammation preceded retinal degeneration in CNGB1 mice.

Thus, it can be argued that patients with IRDs may be predisposed to inflammation, and adeno-associated virus (AAV)–based gene therapy in these patients may trigger severe inflammatory responses that can lead to permanent visual loss in some.

In phase 1/2 trials of gene therapy for RPE65-associated Leber congenital amaurosis, choroideremia, and RPGR-associated X-linked RP, ocular inflammation was dose-dependent, Kay pointed out, with patients receiving higher doses at higher risk for vitritis, retinitis, and choroiditis.

“At . . . best . . . gene therapies treat disease and restore/rescue function,” Kay explained. “At worst . . . [they introduce] a new antigen and creat[e] a new problem.”

Among the numerous factors that stimulate inflammation are delivery mode, vector/capsid manufacturing, promoters and transgene expression, surgical considerations, host characteristics, and dose (the most clinically relevant inflammation occurs with doses of 1 x 1011 vg/eye or higher).

The immune response varies according to the mode of administration (subretinal vs intravitreal). Most trials today evaluate vectors injected subretinally, whereas suprachoroidal injections are used less frequently.

“Intravitreal delivery . . . is [generally] more inflammatory than subretinal delivery and can lead to increased aqueous vector levels, increased systemic biodistribution to spleen/lymph nodes, [and] increased systemic dissemination from . . . anterior chamber [outflow],” Kay said. This dissemination, in turn, can trigger more “neutralizing antibody responses, which can interfere with effective transgene expression and lead to greater humoral responses and . . . reduced therapeutic efficacy.”

Regarding the vector capsid serotype, baseline immunity can be species-dependent. Dose-dependent increases in binding and neutralizing antibodies after AAV injection and in increased serum levels of binding antibodies appear to be correlated with inflammation. But injection dose is the most important factor affecting increased serum antibody level.

In terms of the roles that vector design and manufacturing play in inflammation, we need to know more about the effects of the production platform (triple transfection in HEK293 cells and herpes- and baculovirus-based systems), of the empty capsid ratio (which correlates with increased transduction efficiency), and of process residuals and contaminants. Nevertheless, as previously noted, it is vector dose that correlates most closely with the inflammatory response.

A strong correlation has been observed between AAV toxicity and cis-regulatory sequences.

 As Xiong et al report, ubiquitous promoters (retinal pigment epithelial promoters) were more toxic than photoreceptor-specific promoters. The reason may be that ubiquitous promoters drive higher levels of transgene expression in more cell types.

Surgical delivery of AAV plays a role in inflammation. Proinflammatory factors of surgery include variability in bleb size, location, and dilution with BSS; surgery-related adverse events (particularly hemorrhage); operative duration; and vitreous egress of the vector.

These include patient age, pigmentation, immune system hyperactivity, human leukocyte antigen type, and neutralizing antibodies. AAV can immediately activate innate pattern recognition receptors that lead to the release of inflammatory cytokines and type I interferons. A delayed (adaptive) immune response occurs days or weeks after innate immunity. A cellular response can result in increased T cells and a humoral response in increased B cells, plasma cells, and antibodies.

In the battle between AAV and the immune system, these are the important points to remember.

Although inflammation is par for the course in ocular gene therapy, ophthalmologists rarely discuss it.

Inflammation occurs with subretinal as well as intravitreal injections.

It may be subtle (subretinal deposits seen on an OCT) and may be correlated with loss of therapeutic efficacy.

It is typically dose-dependent, can manifest in multiple ways, and can occur and recur in adults.

Preventing inflammation should be the goal because once it develops, treatment can be difficult and require long-term management and extensive interventions.

Optimization of capsid design for low empty capsid ratio, a clean manufacturing profile, and promoter choice are needed.

Intelligent and target-specific choice of immunosuppressant management including general agreement on corticosteroid use, alternative steroid-sparing immunosuppression if a specific therapy requires long-term management, and use of periocular steroid injection seems to become routine in subretinal trials, but with potential accompanying risks of cataract and glaucoma.

Because “our primary responsibility as physicians is to do no harm . . . we need to acknowledge inflammation in AAV-based gene therapy . . . discuss it, and learn . . . to control it,” Kay concluded.

This article was adapted from Christine Kay’s presentation at the 25th annual meeting of the American Society of Gene & Cell Therapy in May 2022. Kay is an investigator for and consultant to numerous companies involved in retinal gene therapy research.

1. Blank T, Goldmann T, Koch M, et al. Early microglia activation precedes photoreceptor degeneration in mouse model of CNGB1-linked retinitis pigmentosa. 

. 2018;8:1930-1940. doi:10.3389/fimmu.2017.01930

2. Bainbridge JWB, Mehat MS, Sundaram V, et al. Long-term effect of gene therapy on Leber’s congenital amaurosis. 

. 2015;372:1887-1897. doi:10.1056/NEJMoa1414221

3. Xue K, Jolly JK, Barnard AR, et al. Beneficial effects on vision in patients undergoing retinal gene therapy for choroideremia. 

. 2018;24(10):1507-1512. doi:10.1038/s41591-018-0185-5

4. Cehaic-Kapetanovic J, Xue K, Martinez-Fernandez de la Camara C, et al. Initial results from a first-in-human gene therapy trial on X-linked retinitis pigmentosa caused by mutation in RPGR. 

. 2020;26(3):354-359. doi:10.1038/s41591-020-0763-1

5. Bucher K, Rodríguez-Bocanegra E, Dauletbekov D, et al. Immune responses to retinal gene therapy using adeno-associated viral vectors—implications for treatment success and safety. 

. 2021;83:100915. doi:10.1016/j.preteyeres.2020.100915

6. Timmers AM, Newmark JA, Turunen HT, et al. Ocular inflammatory response to intravitreal injection of adeno-associated virus vector: relative contribution of genome and capsid. 

. 2020;31(1-2):80-89. doi:10.1089/hum.2019.144

7. Xiong W, Wu DM, Xue Y, et al. AAV cis-regulatory sequences are correlated with ocular toxicity. 

. 2019;116(12):5785-5794. doi:10.1073/pnas.1821000116

Articles

Causes of ocular inflammation linked to AAV gene therapy 

Research led by scientists at Mass Eye and Ear and Brigham and Women’s Hospital, member hospitals of Mass General Brigham, uncovers the role that a genetic variant linked with Alzheimer’s disease, 

According to a news release from Mass Ear and Eye, in the study published August 16 in 

 the researchers also used a pharmacologic treatment to successfully prevent the destruction of neurons in the eyes of mice with glaucoma by targeting the 

 gene variant, which increases risk for Alzheimer’s but decreases risk of glaucoma in humans, blocks a disease cascade that leads to the destruction of retinal ganglion cells in glaucoma.

Additionally, the team demonstrated in separate mouse models that the death of retinal ganglion cells – the cause of vision loss in glaucoma – can be prevented by using medications to inhibit a molecule called Galectin-3, which is regulated by the 

 gene. These findings taken together emphasize the critical role of APOE in glaucoma and suggest that Galectin-3 inhibitors hold promise as a glaucoma treatment, according to the authors.

Milica Margeta, MD, PhD, a glaucoma specialist and scientist at Mass Eye and Ear, and assistant professor of ophthalmology at Harvard Medical School, pointed out in the news release that the team’s research offers a greater understanding of the genetic pathway that leads to irreversible blindness in glaucoma, and also points to a possible treatment to address the root cause of the vision loss.

“This study shows that the APOE-mediated disease cascade is clearly harmful in glaucoma, and that when you interfere with it genetically or pharmacologically, you can actually stop the disease,” Margeta said.

Understanding and halting the cause of vision loss in glaucoma

According to the news release, glaucoma is a leading cause of blindness, affecting an estimated 80 million people worldwide. While the disease is quite common, little is known about the underlying mechanisms that lead to the loss of retinal ganglion cells, which ultimately results in vision loss. As a result, there is no treatment to directly promote survival of these cells; current treatments, including medications, laser therapies and surgeries are aimed at lowering eye pressure, the only modifiable risk factor for glaucoma. However, the disease often progresses despite these interventions and can result in complete blindness.

Scientists have suspected that glaucoma may be the result of a microscopic inflammatory process in the eyes. Previous studies by this research team and others, showed that this inflammatory process occurs in the optic nerve of glaucoma patients, as indicated by the presence of activated microglia, which are cells that act as first-line immune responders in the eye and brain. Microglia can be beneficial in healthy tissue; however, in eye diseases and neurodegenerative conditions like Alzheimer’s and Parkinson’s disease, microglia can produce toxic molecules, destroy living neurons, and make neighboring cells become inflammatory.

Oleg Butovsky, PhD, with the Department of Neurology at Brigham and Women’s Hospital, was the principal investigator in a landmark study 5 years ago that found that in neurodegenerative diseases, including Alzheimer’s, amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS), microglia switch to a microglial neurodegenerative phenotype (MGnD), which is mediated by the 

 (Apolipoprotein E) gene. It is well established in neurological research that one variant of this gene, called 

, is linked to an increased risk for late-onset Alzheimer’s disease. In a twist, an earlier study led by Margeta, 

 is tied to a decreased risk of developing glaucoma, but it was not understood why. 

The new study led by Margeta and Butovsky, sheds light on this mechanism. The scientists used RNA sequencing to provide an unbiased look at which genes were turned on and off in microglia in different mouse models with glaucoma. They identified a disease cascade in which APOE controls the microglial transition from a healthy cell to a toxic neurodegenerative cell by regulating another molecule called Galectin-3.

When researchers attempted to induce glaucoma in a mouse with the 

 variant, they found despite the expected elevated eye pressure, the microglia were unable to turn on this toxic cascade and did not produce Galectin-3, instead remaining in a homeostatic state with preservation of retinal ganglion cells.

According to the news release, the same results were detected in mice without 

: the toxic signaling cascade was not turned on, Galectin-3 was not produced, and neurons were protected. The scientists also analyzed human eye tissue samples provided by Duke University Medical Center and confirmed that Galectin-3 was increased in the retina of glaucoma patients with the common 

 variant but was almost undetectable in patients with 

“This was a striking finding and led to testing whether a pharmacologic intervention could block Galectin-3, which could potentially treat glaucoma,” explained Butovsky, the senior study author and also an associate professor of neurology at Harvard Medical School.

The scientists used Galactin-3 inhibitors, which can be derived from natural sources and are currently in clinical trials for the lung disease pulmonary fibrosis. They found that injecting these inhibitors inside the eye blocked the disease cascade in mice with glaucoma, and the retinal ganglion cells were protected despite elevated eye pressure.

“Our findings provide an explanation as to why APOE4 is associated with a decreased risk of glaucoma and show that the APOE signaling pathway is a promising target for neuroprotective treatments for this blinding disease,” Butovsky explained. “However, why the same allele is deleterious in Alzheimer’s disease but protective in eye neurodegenerative diseases has yet to be addressed.”

This study is the first to examine the role of Galectin-3 in the development of glaucoma and to show the value of inhibiting this molecule in order to prevent retinal ganglion cell death.

Future studies by this research team will look more closely at Galectin-3 inhibitors as treatments for glaucoma, testing them in additional animal models as well as looking at more minimally invasive approaches of inhibitor delivery, such as oral administration or in a slow-release gel.

Ongoing studies are also examining eye fluid and serum samples collected from patients during glaucoma surgery to better understand the patient population in which Galectin-3 inhibition would be a potential therapeutic approach. For example, if Galectin-3 is found to be elevated in the biofluids of a patient, it could suggest that he/she could be a candidate for treatment with the inhibitor medication. Such studies can pave the way to translate this research into human clinical trials, according to the authors.

Moreover, Joan W. Miller, MD, chief of ophthalmology at Mass Eye and Ear, Massachusetts General Hospital and Brigham and Women’s Hospital, and Chair of Ophthalmology and the David Glendenning Cogan Professor of Ophthalmology at Harvard Medical School, lauded the scientists’ efforts.

“Glaucoma remains a blinding disease for millions of people around the world, and these exciting findings by Drs. Margeta and Butovsky and team provide insight into the role of genetic variants, and the promise of translation to a treatment for patients,” Miller noted.

According to the news release, Butovsky and his lab are conducting research examining the APOE microglial cascade and the role of 

 variant in microglial regulation in Alzheimer’s disease.

In addition to Margeta and Butovsky, co-authors on the study included Zhuoran Yin, MD, PhD, Charlotte Madore, PhD, Kristen M. Pitts, BA Sophia M. Letcher, BA, Jing Tang, MD, Shuhong Jiang, MD, Christian D. Gauthier, MS, Sebastian R. Silveira, BA, Caitlin M. Schroeder, BA, Eleonora M. Lad, MD, PhD, Alan D. Proia, MD, PhD, Rudolph E. Tanzi, PhD, David M. Holtzman, MD, Susanne Krasemann, PhD, and Dong Feng Chen, MD, PhD.

The news release also noted that the study was funded, in large part, by the Cure Alzheimer's Fund, National Institutes of Health’s National Eye Institute and National Institute of Neurological Disorders and Stroke, the BrightFocus Foundation, the American Glaucoma Society Young Clinician Scientist Award and a Research to Prevent Blindness Career Development Award.

1. Milica Margeta, MD, PhD, and Oleg Butovsky, PhD, et.al; Apolipoprotein E4 impairs the response of neurodegenerative retinal microglia and prevents neuronal loss in glaucoma. 

, published online Aug. 16, 2022. DOI: https://doi.org/10.1016/j.immuni.2022.07.014

APOE4 gene associated with Alzheimer’s disease risk was found to protect mice from glaucoma. Research team also prevented retinal ganglion cell death by blocking the APOE signaling pathway, pointing to a potential treatment strategy for glaucoma.

Study: APOE gene linked to Alzheimer’s may prevent retinal ganglion cell death

X-linked retinoschisis (XLRS) is a congenital disorder that results in visual impairment in boys at an early age. No treatment is currently available, and surgical repair fails in many cases. Retinal damage in the periphery includes tears and retinal surface bubbling, scarring, and fibrosis.

XLRS affects the retina both structurally and functionally, ie, splitting of the retinal layers across the macula and periphery and cysts present; an increased risk for hemorrhage and detachment; and on electroretinography (ERG), interrupted transmission from the a-wave to the b-waves (from the rods to the bipolar cells) and reduced or lost ERG b-wave. The retinoschisin 1 (RS1) protein is localized to the rod inner segment and the outer plexiform layer synapses.

Investigators have reported good progress in determining how the disease works in the eye; however, a downside is the inflammation that seems to accompany treatment with increased dosing. Paul Sieving, MD, PhD, described recent study outcomes and focused on the inflammatory component associated with treatment. Sieving is the Neil and MJ Kelly Presidential Chair and director of the Center for Ocular Regenerative Therapy at University of California, Davis in Sacramento.

The XLRS protein is not exclusive to the eye, according to Sieving, and is found in the lung as well.

 Other authors suggested the role of the protein in lung carcinoma; they found that in lung adenocarcinoma, the prognosis is worse if the tissue has low expression of RS1 protein, indicating that the protein may be seen by the systemic circulation,

Regarding the protein localization, investigators reported that an element of the synapses, the trip channel (conductance channel) was found to be missing in Rs1 knockout retinas in mice, which impairs signaling of the synapses to the bipolar cells.

 After therapy, in a normal retina, the molecules of the signaling cascade are tightly localized to the dendritic tips; in contrast, in the knockout model, the molecules are delocalized along the shaft of the dendrites.

In Sieving’s laboratory where they constructed a knockout transgenic mouse model that replicated human disease, ERG images showed the presence of the a-wave and the absence of the b-wave.

The investigators then created a vector to treat this scenario and injected it into the middle of the vitreous. They found Rs1 protein expression in the wild-type mouse retina and in the AAV-Rs1 vector-treated retinas, in which the Rs1 expression was restored and the schisis cavities were absent; however, the untreated knockout retina showed schisis cavities and no Rs1 expression, Sieving reported.

Likewise, the retinal structure was restored after the vector treatment, and the b-wave recovered.

The next step in Sieving’s research involved testing the vector injected into the vitreous in a human phase 1/2a clinical trial.

 Four doses were tested (1e9-3e11) in 12 patients. He reported one particular patient of interest who had cavities before dosing, but the cavities were sealed shut by 14 days after dosing. “We are viewing this result as some evidence of biologic activity,” he commented.

The first 2 lower doses in the phase 1/2a study were not associated with inflammation. Last-onset inflammation developed in one patient who received dose 1e10 that resolved with oral steroid therapy; another patient had preexisting neutralizing antibody and had a very strong antibody response that was maintained without signs of clinical inflammation.

Three patients on the highest dose had varying degrees of ocular inflammation; pretreatment with a steroid was not administered to 2 patients but was administered to the third patient, who despite the pretreatment developed “considerable” inflammation, but the cavities closed. “This means that ocular inflammation cannot always be averted despite predosing with steroids,” Sieving said.

The next step was a return to the mouse model to study the retina transcriptome at baseline and after dosing. The findings were interesting because a young mouse had many upregulated genes associated with immune system processes. “This indicated that there is preexisting immune activation in the retinas with retinoschisis,” he pointed out.

After vector treatment, the upregulation was moderated, and wound-healing genes were upregulated with movement toward a recovery phase.

This raised the question about whether baseline inflammatory disease contributes to a vector immune response.

An investigation5 into serum samples from 11 human patients dosed with the vector showed serum markers before vector dosing, ie, CD4+ T cells were upregulated, and CD8+ T cells were downregulated.

The ratio of the 2 cell types was increased at baseline and represents a marker of immune activation.

Again, a question arose about whether baseline inflammation from retinal degeneration causes a pro-inflammatory response to the AAV vector.

Sieving reported that the degree of inflammation after vector treatment in these patients was correlated roughly with the baseline CD4+/CD8+ cell level. In addition, cytokines and interferon-γ levels also were upregulated after vector treatment, which was unexpected because these are systemic immune markers.

Based on this small study, Sieving had the following takeaways:

Patients who received the same vector doses showed considerable variability in response and inflammation.

Pretreatment with a steroid did not abrogate the immune response.

Pretreating with immune suppression appeared to reduce the immune response and inflammation in 1 of 2 patients.

The highest dose of the vector provided preliminary signs of retinal biologic activity.

A question for future research is the immune baseline status and how an ocular disease is reflected in the blood/plasma compartment.

This article is adapted from Sieving’s presentation at the American Society of Gene and Cell Therapy 25th Annual Meeting in Washington, DC. He is a cofounder of VegaVect, Inc and Avista Therapeutics and on the scientific advisory boards of SparingVision and the Institute of Molecular Ophthalmology Basel.

1. Tolun G, Vijayasarathy C, Huang R, et al. Paired octamer rings of retinoschisin suggest a junctional model for cell-cell adhesion in the retina. Proc Natl Acad Sci U S A. 2016;113(19):5287-5292. doi:10.1073/pnas.1519048113

2. Zhang T, Cheng G, Chen P, et al. RS1 gene is a novel prognostic biomarker for lung adenocarcinoma. Thorac Cancer. 2022;13(12):1850-1861. doi:10.1111/1759-7714.14471

3. Ou J, Vijayasarathy C, Ziccardi L, et al. Synaptic pathology and therapeutic repair in adult retinoschisis mouse by AAV-RS1 transfer. J Clin Invest 2015;125(7):2891-2903. doi:10.1172/JCI81380

4. Cukras C, Wiley HE, Jeffrey BG, et al. Retinal AAV8-RS1 gene therapy for X-linked retinoschisis: initial findings from a phase I/IIa trial by intravitreal delivery. Mol Ther. 2018;26(9):2282-2294. doi:10.1016/j.ymthe.2018.05.025

5. Mishra A, Vijayasarathy C, Cukras CA, et al. Immune function in X-linked retinoschisis subjects in an AAV8-RS1 phase I/IIa gene therapy trial. Mol Ther. 2021;29(6):2030-2040. doi:10.1016/j.ymthe.2021.02.013

X-linked retinoschisis is a congenital disorder that results in visual impairment in boys at an early age. No treatment is currently available, and surgical repair fails in many cases. 

AAV-RS1 trials for X-linked retinoschisis: the good, the bad, and the inflamed

Oyster Point Pharma Inc. today announced that the largest Medicare pharmacy benefit manager in the United States will add its varenicline solution nasal spray (Tyrvaya) for the treatment of dry eye on its Medicare Part D formularies, effective September 1.

According to Jeffrey Nau, PhD, MMS, president and CEO of Oyster Point Pharma, the milestone will further expand patient access and enable continued momentum in eye care professionals prescribing the nasal spreay for the treatment of dry eye disease.

“In the United States, almost half of the total dry eye disease prescriptions are covered by Medicare, and we believe TYRVAYA provides a truly compelling treatment option,” he said in a statement. “We are committed to growing patient access and are looking forward to continue engaging with Medicare Part D health plans.”

The FDA in Ooctober 2021 approved the varenicline solution nasal spray for the treatment of the signs and symptoms of dry eye disease.

According to the company, varenicline solution nasal spray 0.03 mg is a selective cholinergic agonist that is FDA-approved to treat the signs and symptoms of dry eye disease as a multidose nasal spray. The parasympathetic nervous system, the "rest and digest" system of the body, controls tear film homeostasis partially via the trigeminal nerve, which is accessible within the nose.

The company noted that the efficacy of the spray in dry eye disease is believed to be the result of varenicline's activity at heteromeric sub-type(s) of the nicotinic acetylcholine (nACh) receptor where its binding produces agonist activity and activates the trigeminal parasympathetic pathway resulting in increased production of basal tear film as a treatment for dry eye disease. Varenicline binds with high affinity and selectivity at human α4β2, α4α6β2, α3β4, α3α5β4 and α7 neuronal nicotinic acetylcholine receptors. The exact mechanism of action is unknown at this time.

Oyster Point Pharma announces varenicline solution nasal spray for treatment of dry eye to be covered by key Medicare pharmacy benefit manager

A team of investigators has found that myopic refractive error is linked with an increased risk of primary open-angle glaucoma (POAG), and they content the connection has a genetic foundation.

The study, published in JAMA Ophthalmology,

 found that it is imperative to identify any factors that could impact a patient’s POAG risk, and those can include pre-existing genetic risks.

As part of their study of genetic links, the investigators conducted their research using methods that rely upon variation in genes with known functions to study causal effects of a modifiable exposure on an outcome. They noted that the study was a 2-sample Mendelian randomly assigned study evaluating the shared genetic influences, and investigating the link of myopic refractive error and POAG.

According to the study, investigators included 154,018 participants from the UK Biobank and Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort.

Investigators also noted that the observational analyses included data for 54,755 non-Hispanic white individuals (31,926 females and 22,829 males), among which were 4,047 POAG patients and 50,708 controls. According to the investigators, POAG patients had a lower refractive mean spherical equivalent and had an increased likelihood to have myopia or high myopia vs. controls (myopia: 40.2% vs. 34.1%; high myopia: 8.5% vs. 6.8%).

Moreover, the investigators pointed out in the study that the genetic correlation analysis found that POAG was genetically correlated with mean spherical equivalent refractive error, myopia and high myopia. They also indicated that genetically assessed refractive mean spherical equivalent typically was negatively linked with a risk of POAG.

The investigators further noted in the paper that the results support the use of refractive error as a metric to help determine the risk of POAG in the general population.

“Currently, general population screening for glaucoma is not recommended in part due to the relatively low prevalence of undetected cases,” the investigators wrote in the paper. “Understanding which factors increase risk of POAG can help inform strategies for identifying glaucoma-enriched populations for targeted screening, which would lead to earlier diagnosis and preventative strategies for high-risk individuals.

Moreover, the investigators noted that the results also can assist in the clarification of the links between myopic refractive effort and POAG, leading to basing the identification of future POAG risk on refractive error information, which could ultimately lead to earlier diagnosis and preventative strategies for high-risk individuals.

“Clarifying the nature of the association between refractive error and POAG may open new avenues of investigation into specific mechanisms underlying these vision disorders,” investigators concluded.

1. Choquet H, Khawaja AP, Jiang C, et al. Association between myopic refractive error and primary open-angle glaucoma: a 2-sample Mendelian randomization study. 

. Published online July 28, 2022. doi: 10.1001/jamaophthalmol.2022.2762

A team of investigators has found that myopic refractive error is linked with an increased risk of primary open-angle glaucoma, and they indicate that the connection has a genetic foundation. 

Investigators find link between myopia, POAG risk

Sight Sciences Inc. today announced 36-month post-surgery follow-up results of its surgical system (Omni). The data demonstrates that the OMNI Surgical System delivers safe, consistent, and durable results in adult patients with open-angle glaucoma (OAG) on a standalone basis.

According to the company, the study showed that canaloplasty followed by trabeculotomy using the surgical system achieved a mean reduction in intraocular pressure (IOP) of at least 20 percent for all 26 patients (38 eyes) at 36 months follow-up. At 12, 24 and 36 months after surgery, patients’ mean preoperative IOP post medication washout decreased from 24.6±3.2 mmHg to 14.5±1.7 mmHg, 14.2±2.0 mmHg and 15.0±1.9, respectively. The mean number of IOP-lowering medications was reduced from 1.9±0.7 to 0.4±0.6, 0.6±0.7 and 0.5±0.7 at 12, 24 and 36-months.

The postoperative IOP and medication use reduction at 12 months remained consistent over three years, suggesting robust durable effectiveness of the surgical system when used as a standalone intervention either in phakic or pseudophakic eyes. Only a minimal number of adverse events were reported, all of which resolved without any intervention except one eye required secondary IOP lowering intervention.

“As we continue to evaluate this patient group with the OMNI Surgical System, the results consistently show the minimally invasive procedure has the potential to offer long-standing benefits for patients with open-angle glaucoma,” said Karsten Klabe, MD, Principal Investigator, head surgeon of Breyer, Kaymak & Klabe Augenchirurgie. “Most patients experienced an IOP reduction of at least 20 percent and required significantly less medication, meeting the study's objective. By effectively reducing IOP and the medication burden, the OMNI Surgical System is transforming how glaucoma is cared for in both combination cataract and standalone glaucoma patients.”

The company noted in its news release that the clinical observation included 38 eyes from 26 patients with OAG treated with the surgical system. Follow-up visits were done on day 1, week 1 and months 1, 3, 6, 12, 18, 24, 30 and 36 after surgery. This trial is an extension of 24-month data that was published in 

Paul Badawi, co-founder and CEO of Sight Sciences, noted in the news release that the company’s surgical system is supported by a robust clinical development program, which includes this treatment evaluation over 3 years in patients with open-angle glaucoma.

“These results highlight the long-term effectiveness and strong safety profile of the OMNI Surgical System,” Badawi explained in the release. “This non-implantable procedure has shown effectiveness without the known IOP-lowering assistance of cataract surgery. We look forward to ongoing data collection and evaluating the durability at further intervals post-microinvasive canal surgery with OMNI.”

The data results were presented in June at the 15th European Glaucoma Society (EGS) Congress in Athens, Greece.


1. Klabe K, Kaymak H. Standalone Trabeculotomy and Viscodilation of Schlemm’s Canal and Collector Channels in Open-Angle Glaucoma Using the OMNI Surgical System: 24-Month Outcomes. Published July 2021: 3121-3129. 

According to the company, a study shows the non-implantable minimally invasive glaucoma surgery effectively reduces IOP and reduces need for IOP-lowering medications in patients diagnosed with open-angle glaucoma.

Sight Sciences releases long-term safety, efficacy data of standalone use of Omni surgical system in patients with open angle glaucoma

Palatin Technologies Inc. today announced the results of a planned interim analysis of the Phase 3 pivotal study of PL9643 (MELODY-1) in patients with dry eye disease (DED).

According to the company, the interim analysis included an assessment and review by the independent Data Monitoring Committee (DMC) of the efficacy and safety of the first 120 patients who had completed treatment. Based on their review, the DMC recommended the study continue with a study sample size target of up to 350 patients. No safety concerns were identified by the DMC.

The company noted in its news release that the DMC's primary objective was to provide a recommendation on the final sample size based on an interim assessment using a conditional power modeling approach. The DMC had the option to recommend a final sample size of up to 600 patients.

According to the news release, the DMC performed its assessment on the first 120 patients to complete the study and based on their recommendation, Palatin plans to enroll up to an additional 230 patients in the study for a final sample size of 350 patients. Topline results are expected in the second quarter of calendar 2023.

Carl Spana, PhD, president and CEO of Palatin, pointed out that the company was encouraged by the DMC's recommendation to continue enrolling patients in this ongoing trial.

“The emerging data, including the safety and ocular tolerability, indicate that PL9643 could be a potentially safe and effective treatment for patients with DED," Spana said in the news release. “Based on trial results to date, we believe PL9643, with its differentiating factors, could provide a fast-acting and well-tolerated treatment option for the millions of patients suffering from DED, and we look forward to presenting topline results of this Phase 3 trial in the second quarter of calendar 2023."

The pivotal Phase 3 MELODY-1 clinical study is a multi-center, randomly assigned, double–masked and vehicle–controlled study evaluating the safety and efficacy of the melanocortin agonist, PL9643 ophthalmic solution, compared to vehicle in patients with moderate-to-severe DED.

According to the news release, the study design is based on positive Phase 2 results of PL9643 for the treatment of DED, and an end-of-phase 2 (EOP2) meeting with the U.S. Food and Drug Administration (FDA), reaching agreement on all key elements of a pivotal Phase 3 clinical program.

Dry eye disease is estimated to affect over 20 million people in the United States. Existing therapy for DED is generally regarded as inadequate by many physicians and patients, and often requires weeks or months to demonstrate activity.

According to the news release, Palatin Technologies focuses on developing medicines based on molecules that modulate the activity of the melanocortin and natriuretic peptide receptor systems.

The melanocortin receptor ("MCr") system has effects on inflammation, immune system responses, metabolism, food intake, and sexual function.

The company noted that there are five melanocortin receptors, MC1r through MC5r. Modulation of these receptors, through use of receptor-specific agonists, which activate receptor function, or receptor-specific antagonists, which block receptor function, can have medically significant pharmacological effects.

Many tissues and immune cells located in the eye (and other places, for example the gut and kidney) express melanocortin receptors, empowering our opportunity to directly activate natural pathways to resolve disease inflammation.

An independent data monitoring committee recommends continuing study with a sample size target of up to 350 Patients. According to the company, no safety concerns have been identified and topline results are expected during the second quarter of 2023. 

Palatin reports positive interim analysis in Phase 3 pivotal study of potential therapeutic for patients with dry eye disease

 In our field, we have on-label biologics: ranibizumab, aflibercept, brolucizumab, and faricimab. But for many years, we’ve been using off-label bevacizumab injected in the eye and have had, more or less, a good experience with it and its efficacy and safety. There are now biosimilars to bevacizumab. The [American Academy of Ophthalmology] got involved because payers started to encourage, or mandate, I’m not sure what they actually did, but there was something that was put out there that we should be using these in the eye.

 That’s crucial to understand because when we look at these biosimilars for bevacizumab, we must realize that these are different in terms of the excipients. It hasn’t been tested in the eye. The Academy of Ophthalmology policy statement says we must be very careful, we can’t just take a drug that’s never been used in the eye just because it is biosimilar to bevacizumab. Specifically when we look at these, we must test that biosimilar in the eyeball; we can’t take these off the shelf and say, “Oh, well, it’s bevacizumab,” and inject it into the eyeball. We must have studies, this is what the academy says. With bevacizumab, we have the CAT trial that showed that it was safe. We also have the DRCR.net [Diabetic Retinopathy Clinical Research Network] studies that compared a bevacizumab formulation, as given, to the other drugs that are out there. We don’t have this for the biosimilars for bevacizumab. As of today, I want to make sure everybody realizes we can’t just formulate these. It’s very important that the insurance companies do not make us use this because it could be disastrous in the eye.

 The FDA standards for safety and purity of a product to be used intravenously or systemically is different than the eye. The eye is, in essence, a more sensitive organ system, so what may be tolerated intravenously may not be in the eye. The academy has made an official statement that we should not be using a biosimilar of bevacizumab–which was biosimilar for systemic administration–to be used in the eye.

 Exactly, because of the excipients, the other things that are the nonbiologic portions that can have disastrous effects in the eye.

 An important distinction. One other interesting or unique aspect to a biosimilar is that the equivalency studies that we’ve been talking about were testing the product against the reference product in 1 specific disease state. The 2 studies we talked about were for neovascular AMD [age-related macular degeneration], and yet the approval could potentially be for more or other conditions, is that right?

 That’s right. This is the difference with these biosimilars. Once you prove that a drug is biosimilar, the biosimilar is equivalent to the reference drug, you then gain the indications that the reference drug already had. Specifically, for SB11, which was shown to be equivalent to ranibizumab, this was a dose of ranibizumab 0.5 mg. All the indications that ranibizumab 0.5 mg has, you can use SB11 for; so that is, neovascular AMD, retinal vein occlusion, and myopic CNV [choroidal neovascularization]. You’re probably wondering, can I use it for diabetes? The answer is no because that was 0.3 mg ranibizumab for the approval, so that is not yet out there.

 At least in the United States, yes, right, because they do use 0.5 mg in Europe. If you live in Europe, you can use it.

Videos

Carl D. Regillo, MD, and Jennifer I. Lim, MD, caution against the ophthalmic use of biosimilar products approved for systemic use. They also review how indications for biosimilars are granted upon approval.

Biosimilar Indications and Routes of Administration

 Jenny, so far, we have 1 FDA-approved biosimilar of ranibizumab, and it’s now commercially available. Any and all of us could be using this product, and maybe some of the others coming very soon. Let’s take a deeper dive into the clinical trials.

 Our fields know clinical trials, the results. Can you tell me what the clinical trials showed that led to the approval of SB11? The proof is in the pudding.

 Absolutely. We love data, and I’m going to give it to you. In terms of the efficacy of SB11, looking at that sensitivity curve at the first 8 weeks when they compared SB11 to the reference drug, ranibizumab, the change in best corrected visual acuity was 6.2 for SB11 and 7.0 for ranibizumab, so essentially the same, no significant difference. In terms of the central subfield thickness change, which was required at 4 weeks for the European medical approval—unlike the FDA requiring the 8-week visual acuity change for approval—the difference was a decrease of 108 μm for SB11 compared to a difference of 100 μm for ranibizumab, again, no significant difference. That tells me, in terms of visual acuity and central subfield thickness change, it’s equivalent.

 That’s what we need to hear, right? Same efficacy, for sure. They also do drug-antibody testing; how did that come out? What did it show?

 Antidrug antibodies are very important when you talk about biologics because they’re produced by E. coli cells in the process, so technically, you can develop antibodies to this. We can feel comfortable because in this study, for SB11 compared to ranibizumab, the antidrug antibodies did not significantly differ. It was 3% for SB11 and 7% for ranibizumab, so no significant difference there.

 Going back to nocebo, but on the safety side, we’re super sensitized because of some of these issues we talked about before, that some biologics have had higher rates of intraocular inflammation [IOI], and some of those were severe and even led to vision loss. The biologics and on-label drugs we’ve been using, and the reference product we’re talking about here, are squeaky clean, right? Very low rates.

 We’re talking in major clinical studies that led to the FDA approval, no more than 2% for significant intraocular inflammation. How did it turn out in this particular study for SB11?

 It was 0.9% IOI for SB11 vs 0% for ranibizumab, so again, clean. I want to emphasize, and you brought this up, that yes, we do have that history, we can’t negate that. We have 15 years of safety data for ranibizumab, and that’s the only difference now between the biosimilar and ranibizumab, because we must wait and get that data accumulated over years.

 We have another phase 3 equivalency study of another biosimilar. It’s not quite FDA approved, but we expect that to happen sometime soon. Can you tell me about that? Does it look the same?

 It’s looks the same. It was called the COLUMBUS-AMD study, FYB201 compared to ranibizumab, the reference drug. In terms of the visual acuity change and the central subfield change, no significant difference.

 It should be said, these are studies with identical dosing, usually monthly dosing.

 Gold standard approach, head-to-head. It’s a pretty big study, although it’s only 1 equivalency phase 3 study, it’s still big. The study for SB11 was 705 patients in total for the 2 arms. Those are big studies, and that should give us a good level of confidence, right?

Carl D. Regillo, MD, and Jennifer I. Lim, MD, review clinical trial data for biosimilar products, with interpretation of safety data when comparing to the biologic reference products.

Clinical Findings for Biosimilars in the Treatment of Retinal Disorders

Cheryl Guttman is a medical writer based in Deerfield, Ill.

IOLs introduced into the US market during the last 2 years offer cataract surgeons an almost dizzying array of options for pseudophakic correction, said Priyanka Sood, MD.

Sood described the technologies and offered insights shared with her by colleagues who had experience with the various lenses. At bottom, there are pros and cons to consider for each IOL and achieving patient satisfaction depends on careful selection and thorough preoperative counseling.

“The reality is that none of these lenses is the holy grail able to restore prepresbyopic quality vision,” said Sood, an assistant professor of ophthalmology at Emory University in Atlanta, Georgia.

The monofocal category was expanded recently with 2 novel aspheric hydrophobic acrylic lenses ––the TECNIS Eyhance (ICB00, Johnson + Johnson Vision) and the Clareon (Alcon). The Eyhance IOL has “extended depth of focus (EDoF)-like qualities” through the design of the central 1 mm of its optic. However, the Eyhance was not approved as an EDoF lens and surgeons cannot charge a premium fee for it. Outside the central 1 mm, the Eyhance optic is similar to the monofocal ZCB00 (Tecnis, Johnson + Johnson Surgical Vision), which explains its good contrast sensitivity, Sood said.

Katie Petro, MD, told Sood she has had good results with the Eyhance and that patients who have received implants are happy. Petro noted that the extra range of vision it provides is for fingertip or computer distance. Using a mini-monovision approach targeting approximately –0.5 D in the nondominant eye can give more near vision, she said.

The Clareon is built on the AcrySof IQ IOL platform but features a new precision edge design to decrease photic phenomena. A new biomaterial and manufacturing process aim to decrease the development of nanoparticle glistenings.

Sumitra Khandelwal, MD, told Sood that the long history of good quality vision with the AcrySof platform is an advantage for the Clareon lens. In addition, as a monofocal lens, it avoids the drawbacks of diffractive multifocals. Only time will tell if the design and material innovations achieve their respective goals of decreasing photic phenomena and nanoglistenings.

Uptake of the light adjustable lens (LAL) has been slow but is picking up momentum. Some reasons for its late adoption, according to Neda Shamie, MD, may include the equipment cost and the workflow related to extra visits needed to perform the adjustments. The advantage of the LAL is that it gives clinicians the ability to customize and accurately titrate the refractive power to the target for each patient.

“Dr Shamie believes that the LAL is the ideal IOL for any patient desiring a customizable outcome and most definitely the ideal for any postrefractive surgery patients who would otherwise risk the unpredictability of refractive outcomes with a static IOL,” Sood said.

The new IOL in the EDoF category is the AcrySof IQ Vivity (Alcon). The Vivity uses wavefront-shaping technology on its anterior surface that elongates the depth of focus, giving about a 1.5 D range of vision. Because it is a nondiffractive lens, risks of glare and halos are minimized and quality of vision is better than with a multifocal IOL. However, results from the FDA clinical trial showed some loss of contrast sensitivity with the Vivity lens, and it does not give good reading vision.

Pearls shared from colleagues for improving outcomes include targeting –0.25 D in the dominant eye and –0.5 to –0.65 D in the nondominant eye, taking care intraoperatively to ensure the IOL is centered and giving patients time to neuroadapt.

The 2 newest multifocal IOLs––AcrySof IQ PanOptix (Alcon) and Tecnis Synergy (Johnson + Johnson Vision)––almost guarantee a broader range of vision than EDoF IOLs but not the avoidance of photic phenomena, Sood said.

The PanOptix is a trifocal lens with negative spherical aberration on its anterior surface that has diffractive rings in the central 4.5 mm of its optic. For users’ perspective, Sood turned to several colleagues.

According to Dee Stephenson, MD, her patients are achieving great uncorrected vision at all distances. They are truly glasses-free as long as they have a healthy eye and astigmatism is corrected. Audrey R. Talley Rostov, MD, added that the IOL has to be perfectly centered. The downsides of the PanOptix include the potential for glare, halos, and decreased contrast sensitivity at night. Talley Rostov advised avoiding this IOL for patients younger than age 65 because they tend to dislike the decrease in contrast sensitivity.

The Synergy features a hybrid of trifocal and EDoF optic technologies. Experience with this IOL, which is very new to the market, is limited, although early results seem good. Additionally, colleagues outside the United States who have had access to the lens for a longer period of time say that the reading and intermediate vision it provides are better than that provided by other technologies. Distance vision may not be as good as with the PanOptix, however, according to anecdotal reports.

Sood has no relevant financial interests to disclose.

Physician offers "real talk" on pros and cons that offers surgeons and patients decision-making insights.

Biosimilar Indications and Routes of Administration

Clinical Findings for Biosimilars in the Treatment of Retinal Disorders

GA therapy demonstrates continuous, sustained effects of pegcetacoplan over time

SAP Content