Community Practice Connections™: 1st Annual Optometry Times® EyeCon 2021

Optometry EyeCon 

Aerie Pharmaceuticals Inc. today announced that the first participant has been dosed in the Phase 3 registrational COMET-2 study to evaluate AR-15512 ophthalmic solution as a treatment for the signs and symptoms of dry eye disease (DED).

According to the company, COMET-2 (NCT05285644) is the first of three trials in the Phase 3 registrational program for AR-15512. The company said in a news release that it plans to initiate the other two trials in the second half of 2022 in support of a potential New Drug Application (NDA) filing in 2024.

AR-15512 is a first-in-class TRPM8 agonist which acts as a cold thermoreceptor modulator to stimulate the cold sensing receptors found on the nerve endings that innervate the cornea and eyelids. By stimulating these receptors, AR-15512 leads to natural tear production and a cooling sensation across the surface of the eye that may result in a reduction in dry eye symptoms. AR-15512 is a development stage product candidate and is not approved by any regulatory agency.

The company noted that COMET-2 is a randomly assigned, double-masked, vehicle-controlled, multi-center clinical study to evaluate the efficacy and safety of AR-15512, a TRPM8 agonist, in patients with DED.

The study is expected to enroll approximately 460 participants at 20 U.S. sites. Study participants will receive AR-15512 (0.003%) or AR-15512 vehicle as a drop dosed twice daily in each eye for three months. The primary efficacy assessment is tear production, as measured by the unanesthetized Schirmer test (sign), and the key secondary measure is dry eye symptoms based on the Symptom Assessment iN Dry Eye (SANDE) questionnaire.

The company noted that participants will be evaluated on multiple efficacy and safety assessments at multiple timepoints throughout the study. Topline results from the COMET-2 study are expected in the second half of 2023.

Michelle Senchyna, PhD, head of Clinical Development and Medical Affairs at Aerie, added in a news release that Aerie is excited to mark the beginning of its registrational Phase 3 program for AR-15512 with the enrollment of the first participant in the COMET-2 study.

“This study builds on the results of the COMET-1 study which showed statistically significant, dose-dependent improvements on multiple validated sign, symptom, and quality of life endpoints across multiple timepoints,” Senchyna said in a statement.

“There is a significant unmet need for an effective treatment that can provide a rapid and robust onset of efficacy, and meaningful relief of dry eye symptoms,” Senchyna added in the release. “AR-15512 has the potential to be the new standard of care for patients suffering from dry eye disease.”

According to the company, the AR-15512 Phase 3 registrational program is comprised of three studies, the COMET-2 and COMET-3 (NCT05360966) efficacy studies and the COMET-4 safety study, that will evaluate AR-15512 (0.003%) compared to AR-15512 vehicle in participants with DED.

COMET-2, which is currently enrolling, and COMET-3, which is expected to begin in the third quarter of 2022, are identical studies with topline results expected in the second half of 2023. COMET-4, which is expected to begin in the fourth quarter of 2022, is a 12-month safety study. Aerie will incorporate interim 6-month data from COMET-4 into the NDA filing for AR-15512, which is expected to be submitted in 2024.

The COMET-1 study (NCT04498182)evaluated two doses of AR-15512 compared to AR-15512 vehicle in 369 participants with DED. As reported in September 2021, the trial did not achieve Aerie’s previously chosen primary endpoints. The study showed a statistically significant, dose-dependent increase in tear production, a validated endpoint acceptable for registration of a product.

Moreover, the company noted in its release that AR-15512 demonstrated improvements on multiple validated sign, symptom, and quality of life endpoints across multiple timepoints. Importantly, the study showed that differences between AR-15512 and vehicle responses increased over time, indicating a potential sustained, meaningful treatment effect in DED signs and symptoms. COMET-1 demonstrated a favorable tolerability profile with no systemic or serious adverse events attributed to AR-15512.

Articles

The Phase 3 registrational study is examining AR-15512, a differentiated, novel product candidate for the treatment of the signs and symptoms of Dry Eye Disease

Aerie Pharmaceuticals doses first participant in COMET-2 study of dry eye candidate

Across healthcare (and in almost every other industry), when leaders are asked what keeps them up at night, the answer is resoundingly clear: staffing. Although the past few years have seen incredible progress in the adoption and reimbursement for health care technologies like virtual visits and remote patient monitoring (RPM), the issue around people and staffing remains.

As we enter into the third year of the pandemic, we wanted to get a better understanding of the pain points and stressors that health care professionals are experiencing, and how technologies like RPM could better support them and their patients. Late last year, we spearheaded a national survey of providers and office managers across three segments: solo practices, group practices, and hospital-affiliated to learn more about their challenges and triumphs.

What we found: health care solutions need to also address the much bigger problem of staffing shortages and burnout. RPM allows providers to monitor patients’ health outside the office visit, and can alleviate this pressure by allowing practices to grow and scale to support more patients.

Our survey found an inverse relationship between practice size and billing. Many solo providers reported doing their own billing, but as practice size increases, billing/insurance concerns decrease because those are handled by different individuals or departments.

 38% reported that their top stressor is billing or insurance issues

 35% responded that their top stressor is working too many hours/not enough time to complete their work

 69% said their top stressor is adequate staffing/turnover, followed by working too many hours (54%)

Although the numbers of pandemic-related hospitalizations may be falling in many areas across the country and offices are not backlogged with COVID-19 infections, the reality is that burnout and staffing issues are a top concern for different kinds – and sizes – of provider organizations.

When it comes to technology, many are still playing catchup

While the industry sometimes saw seismic shifts in technology adoption such as telehealth and RPM over the past few years, the most recent technology that the vast majority of those surveyed was EHRs and EMRs. The findings reveal a few added telehealth platforms or tools and clinical lab equipment. The data show these organizations are, in many cases, just getting their technology foundation laid with electronic health records.

For technology purchases, lack of resources and clinical outcomes top the list

When diving a bit deeper into a specific technology, respondents reported that they would need to understand how RPM improves clinical outcomes and what staff time and resources are needed to manage a program. Coming in third was revenue opportunities, followed by reimbursement.

When it comes to finding information about new health care technologies, providers and practice managers seek out in-person channels, such as colleagues, peers, conferences or networking events. In a busy tech-driven environment, word-of-mouth referrals can help bring clarity, build trust and carry more weight than social media.

It has always been true that successful technologies address a true industry business problem, and this is especially true for health care and the rise of remote care and RPM technologies. As we provide care through the pandemic, the problems of staffing and burnout are very real and visceral for providers across segments and sizes.

This provides us with an opportunity to solve problems in new ways and leverage technologies like RPM to deliver care in ways that both improve patient outcomes and provider productivity, and hopefully – if we are all successful – reduce the worrying levels of burnout.

Todd Haedrich is the CEO of Optimize Health.

Solutions should address staffing shortages and burnout.

Technology, people key to improving health outcomes, driving revenue

Stealth BioTherapeutics Corp. has announced new data from the ReCLAIM-2 study of elamipretide in geographic atrophy (GA) secondary to dry age-related macular degeneration (dry AMD) at the American Society of Retina Specialists Clinical Trials at the Summit meeting held May 21 in Lake Tahoe, Nevada. 

In a news release, the company noted that the ReCLAIM-2 prespecified analyses demonstrate that elamipretide ameliorated progressive decline, or attenuation, of the mitochondrial rich ellipsoid zone (EZ) layer of the photoreceptors (p < 0.01) and showed a categorical >2-line improvement in low luminance visual acuity (LLVA) (p = 0.04) in patients with GA. Progressive LLVA dysfunction, which is among the first symptoms of dry AMD, compromises patients' ability to see under low-light conditions such as at dusk, in the evening, or indoors using artificial light.

Additional analyses show that, consistent with prior findings from the ReCLAIM Phase 1 study, changes in LLVA correlated with baseline EZ attenuation in ReCLAIM-2. The new analyses also show that elamipretide-mediated reduction of progressive EZ attenuation correlated with improvements in LLVA. Although the trial's primary endpoints of mean change in LLVA and GA progression were not met, these analyses were found to be promising and to support and inform the continued development of elamipretide for dry AMD.

According to the company, dry AMD is a progressive retinal disease in which the photoreceptors, which are specialized neurons found in the retina that convert light into electrical signals required for normal visual function, suffer progressive damage and death, leading to progressive loss of vision. One of the earliest signs of photoreceptor dysfunction is progressive damage to, or attenuation of, the ellipsoid zone (EZ), which is a mitochondrial rich layer of the photoreceptors. EZ attenuation has been shown to precede and predict visual dysfunction in dry AMD and other retinal diseases.

"Preserving the health of structures in the eye needed for visual function, such as photoreceptors, is critical for patients with dry AMD," said Jeffrey Heier, MD, the principal investigator of the ReCLAIM-2 study and director, retina service, and director, retinal research, Ophthalmic Consultants of Boston. "I am pleased to present these data underscoring for the first time the important relationship between mitochondrial health and vision in GA, which we hope will inform future efforts to improve outcomes for patients living with this progressive and irreversible disease."

Elamipretide was generally well tolerated in ReCLAIM-2. The rate of new-onset exudations was 5.3% in the elamipretide treated group versus 6.9% in placebo.

"We are excited to confirm that targeting mitochondrial dysfunction in dry AMD may preserve and potentially improve visual function for some affected patients," Reenie McCarthy, CEO of Stealth BioTherapeutics, said in the news release. "We believe these data can help enrich and inform future development efforts for this devastating disease, and we are evaluating strategies to progress this program, including through potential partnering discussions."

The company is also progressing the clinical development of elamipretide in several rare disease indications as well as advancing a broad pipeline of novel mitochondria-targeting compounds.

According to the company, the ReCLAIM-2 study of elamipretide demonstrates a correlation between ellipsoid zone dysfunction and vision.

Stealth BioTherapeutics announces data from Phase 2 study of geographic atrophy candidate

Ocuphire Pharma Inc. today announced positive topline results from the LYNX-1 (

) Phase 3 pivotal clinical trial investigating its product candidate Nyxol for night (or dim light) vision disturbances (NVD).

According to the company, across 12 US clinical trials with approximately 1100 subjects, over 650 subjects have now been exposed to Nyxol.

NVD is a condition in which unfocused rays of light derived from imperfections (or higher order ocular aberrations) in the periphery of the cornea manifest as reduced image quality when the pupil dilates in dim light conditions. Patients with NVD experience glare, halos, starbursts, and decreased contrast sensitivity.

According to GlobalData market research, approximately 38 million individuals in the US are believed to suffer from NVD, also referred to as dim light vision loss, with an estimated 16 million having moderate-to-severe NVD that may be directly addressable with a pupil modulation approach.

The company noted in a news release that the effects of NVD can be mitigated by moderately reducing pupil diameter to eliminate some of the aberrations and their scattering effect, without impeding the ability to see in dim light due to reduced retinal illumination.

Mina Sooch, MBA, founder and CEO of Ocuphire Pharma, noted in a news release that the company is pleased with the demonstrated efficacy of Nyxol in patients with NVD.

“LYNX-1 represents our 6th consecutive positive data readout for Nyxol in several indications and is a critical milestone towards future product registration,” Sooch said in a statement. “In alignment with our overall clinical priorities, and while we plan for a future LYNX trial as needed next year, we will focus on the pivotal trials for presbyopia and on the NDA submission and pre-commercial activities for Nyxol in reversal of mydriasis (RM).”

Sooch added that the LYNX-1 trial results provide additional support for the safety and vision improvement benefits of Nyxol in RM and presbyopia in dim light conditions.

“We are committed to making a difference for millions of patients with vision problems and are proud of the disruptive innovation we bring to the ophthalmic space,” Sooch concluded in the release. “In that regard, we look forward to yet another late-stage clinical data readout in 2022 from the study of oral APX3330 for diabetic retinopathy.”

The company noted that LYNX-1 is a registration trial for Nyxol in this chronic NVD indication, and was designed as a randomized, double-masked, placebo-controlled, Phase 3 study to evaluate the safety and efficacy of Nyxol compared to placebo.

In the trial, 145 study participants who experienced vision impairment under dim light conditions were randomly assigned to receive either Nyxol or placebo, self-administered in each eye daily, at or near bedtime, over 14 days. The primary endpoint was the gain of 3 lines (or 15 letters) or more of distance vision improvement on a low contrast chart in dim light conditions.

Baseline demographics and ocular characteristic means were well-balanced across Nyxol and placebo treatment arms. Highlights of the patient population include a mean age of 46 years with participants ranging from 19 to 70 years old; subjects with a mix of light and dark irides; mean baseline mesopic pupil diameter of 6.1 mm; and mean distance visual acuity of only 17 letters (20/100 Snellen) under mesopic low contrast conditions.

The FDA-agreed primary endpoint was met, with a statistically significant greater percentage of Nyxol-treated subjects having gained 15 or more letters of mesopic low contrast distance visual acuity (mLCVA) at Day 8, compared to placebo (13% vs 3%; p<0.05)

Key secondary efficacy endpoints were also met with statistical significance:




The effect of Nyxol increased at Day 15, with 21% of subjects gaining 15 or more letters of mLCVA compared to 3% placebo (p<0.01)

Nyxol significantly increased the percentage of subjects gaining 10 or more letters of mLCVA at both Day 8 with 41% vs. 22% placebo (p<0.05) and at Day 15 with 44% vs. 23% (p<0.05)

Nyxol showed a favorable safety and tolerability profile:



Adverse events occurring in Nyxol-treated subjects were predominantly mild in severity and were consistent with those observed in previous trials

According to Jay Pepose, MD, PhD, chief medical advisor and board member, in the past, patients with night vision disturbances sometimes puzzled eye care professionals because their complaints often impacted the quality of vision far more than the quantity of vision as assessed in the office using standard high contrast charts.

“In the LYNX-1 study, after 14 days of dosing, a remarkable 21% of subjects achieved the 3 line improvement, the high bar set by the FDA,” Pepose said in a statement. “Moreover, 44% of subjects gained a clinically meaningful 2 line improvement in mesopic low contrast vision - a test of image quality that is sensitive to higher order aberrations and induced spatial phase shifts seen in patients with night vision disturbances.”

Pepose also noted that the 24-hour duration of Nyxol’s effect in reducing pupil diameter makes this a convenient option for evening dosing for these patients, who find nighttime driving and other dim light activities challenging.

“In distinction to some other classes of miotics, the mechanism of action of Nyxol obviates any increased risk of retinal tears or detachment in this cohort of patients, many of whom have longer axial lengths and are therefore at higher retinal detachment risk,” Pepose concluded. “An additional safety attribute of Nyxol is that it does not make the pupil too small, which can markedly impact retinal illumination and thereby reduce retinal neural contrast and distance vision.”

Moreover, Marguerite McDonald, MD, FACS, a clinical professor of Ophthalmology at New York University’s Langone Medical Center and Tulane University Health Sciences Center, and member of Ocuphire’s Medical Advisory Board, lauded the company for pursuing a treatment option for NVD.

“It is a common condition that has previously been largely unrecognized,” she said in the news release. “I consider the results of the LYNX-1 study to be groundbreaking. As a refractive surgeon who has been involved with the development of Nyxol since its inception, I am happy to have a potential treatment option for my patients who suffer from NVD.”

McDonald pointed out that NVD is currently patient-reported, including people of all ages who are post-LASIK, post-corneal ulcer, post-radial keratotomy, post-corneal transplant, tear-film instability or dry eye disease, keratoconus, or post-cataract surgery with multifocal or extended depth of focus intraocular lens implants.

“Eyecare professionals currently do not have the tools to actively manage NVD,” she said in the release. “Once a treatment becomes available, eyecare providers will begin to address this condition, and we expect that this market may grow, as was the case when Restasis® was approved for dry eye treatment.”

Despite many addressable patients with moderate-to-severe NVD, there is no FDA-approved treatment on the market for NVD. Pupil modulation by Nyxol through inhibition of the iris dilator muscle may offer symptomatic relief for these patients.

According to the company, a clinical trial evaluating Nyxol eye drops for night vision disturbances met FDA-agreed primary endpoint with subjects gaining 3 lines of low-contrast distance vision under dim light conditions compared to placebo.

Ocuphire announces positive topline results from LYNX-1 Phase 3 trial 

Kala Pharmaceuticals Inc. announced that it has entered into a definitive agreement to sell its commercial portfolio and related intellectual property assets to Alcon Inc.

According to a news release, the agreement includes Eysuvis, an FDA-approved medicine for the short-term (up to two weeks) treatment of the signs and symptoms of dry eye disease, and Inveltys, a twice-a-day corticosteroid for the treatment of post-operative inflammation and pain following ocular surgery.

Mark Iwicki, CEO and chairman of Kala, noted that the sale of Eysuvis and Inveltys is a key step forward as part of the company’s strategic plan.

“Alcon is an ideal partner to expand the reach of our commercial assets. Alcon has a decades-long history of delivering market-leading vision care to patients around the world and benefits from robust franchises in dry eye disease and surgical care, making them deeply familiar with eye care professionals and the patients Eysuvis and Inveltysare intended to treat,” he said .”We look forward to working with Alcon through this transition and, ultimately, to devoting our internal resources to developing innovative therapies, including KPI-012, to further transform the treatment of eye diseases.”

Under the terms of the asset purchase agreement, Kala will receive an upfront payment of $60 million and will be eligible to receive commercial-based sales milestone payments. Kala said in the news release it anticipates the transaction will close in the third quarter of 2022, subject to certain conditions, including the expiration of the waiting period under the Hart-Scott-Rodino Antitrust Improvements Act and other customary closing conditions.

According to Kala, the company will now focus on developing KPI-012, a novel cell-free secretome therapy that has the potential to address a number of rare and severe ocular diseases.

Subject to the submission and clearance of an investigational new drug application for KPI-012, Kala expects to initiate a Phase 2/3 clinical trial of KPI-012 for persistent corneal epithelial defect (PCED) in the fourth quarter of 2022 and plans to expand its development program for KPI-012 into additional front and back of the eye indications, with additional details forthcoming in the months ahead.

Following the closing of the sale of its commercial assets, Kala said in the news release that it expects to realize a substantial reduction in operating expenses, which together with the net proceeds from the upfront cash payment received from this transaction, will extend Kala’s operating cash runway into the second quarter of 2024, beyond the expected KPI-012 Phase 2/3 data readout.

Piper Sandler acted as the exclusive financial advisor, and Wilmer Cutler Pickering Hale and Dorr LLP served as legal counsel to Kala.

According to the companies, Kala will receive $60 million in upfront payment, and could be eligible to receive additional sales-based milestone payments. 

Kala reaches deal to sell Eysuvis, Inveltys to Alcon

In the operating room, every second matters. Complications lead to stress, pressure, and clinical and financial consequences. An ideal operating environment is one that helps surgeons and surgical staff make the right decision, at the right time, with minimal physical and cognitive attrition.

At Cleveland Eye Clinic, we perform many cataract and refractive surgeries each day. Investing time, strategy, and resources into improving efficiency has helped us streamline activity, navigate unexpected challenges with poise, and treat more patients, all while delivering quality care. If your organization is looking to do the same, here are some things to remember.

To cultivate efficiency, operating room logistics are your best starting point. Often, we focus primarily on an asset’s clinical value and consider logistics second. In practice, convenience and ease of implementation are mission-critical attributes.

The implementation of tools and devices that come preloaded or precalibrated is a good way to streamline unnecessary activity and preserve both time and focus. Single-use devices have become a staple of cataract and refractive surgery in recent years and represent a step in the right direction. Preloaded intraocular lenses (IOLs) have proven immensely valuable, removing the considerable stress that came with technician loads, syringe management, and associated staff training. Eliminating these staff burdens has given us back time, focus, and energy, which we can gratefully invest in other clinical areas. We frequently use the IPure preloaded monofocal IOL (BVI), which offers high stability in both the short and long term, likely due to the stiffer hydrophobic acrylic material that the lens is made from. Its preloaded injector system is predictable, and efficient.

In our practice, we’ve taken streamlining a step further by having all our surgical tools, including knives, fluid control devices, and more, delivered to our practice in consolidated, procedure-ready packs customized to our specific needs (Beaver Knives and CustomEyes; BVI). This has allowed us to further optimize time and resources, as the time required to set up and take down the surgical suite is greatly reduced. It also eliminates second guessing in the heat of a particularly charged moment; when a critical tool is needed, we know it’s on the table and don’t have to consider the possibility of human error in the setup phase. The custom packs come presterilized and the layers come prefolded according to your exact needs, saving considerable time by eliminating the sterilization step prior to use.

When choosing medications for surgery, it’s also worth thinking about properties that might provide advantages beyond therapeutic efficacy. For instance, we use a compounded, sublingual formulation for subconscious sedation, midazolam/ketamine HCI/ondansetron (MKO Melt; ImprimisRx) in the operating room that reduces or eliminates the need for intravenous-delivered anesthesia, saving nurses (and the health system at large) considerable time and resources. Choosing a medication that effectively negates a preparatory step is an easy way to drive efficiency, but ultimately, you must weigh many factors to determine the best solution for your needs.

Beyond logistics, the surgeon and operating room staff should be able to access and share mission-critical information in an intuitive way. Recently, advanced surgical-suite visualization systems have made this much easier, making it possible to share robust, detail-rich visuals in real time, as well as integrate information from important, normally disparate displays, such as our aberrometer.

Having high-quality information accessible in 1 place, and by the entire surgical team, has made communication easier and more rewarding, helping us deliver outstanding routine care and better manage complications when they arise. In our practice, we have implemented one such system (Ngenuity 3D Visualization System; Alcon), but several are now arriving in the marketplace, including the Beyeonics One (Beyeonics Surgical; distributed by BVI in the US), which includes a removable mount for a noncontact wide-angle near-eye lens for posterior segment surgeries, and the Artevo 800 (Carl Zeiss Meditec), both of which look interesting.

Although patient wellness and clinical outcomes remain our primary goal, staying efficient is an important way to minimize the difficulties, stressors, and costs that arise during a frenetic day in the operating room. By paying attention to logistics and implementing tools that facilitate them—as well as utilizing and communicating the most reliable information possible—we can deliver patients consistent, quality outcomes; improve the experience for our valued staff; and make our own lives easier in the process.

Wiley is in practice at Cleveland Eye Clinic in Northeast Ohio.

Attention to details can help to deliver patients consistent, quality outcomes.

Ophthalmologists drive efficiency in the surgical suite: Why it matters

Investigators from the Department of Ophthalmology, University of Texas Southwestern Medical Center, and the University of Texas Southwestern School of Medicine, Dallas, led by Phillip A. Tensel, MD, reported that in children with unilateral congenital ptosis, the ptotic facial side of the face was the nondominant side of the face. In addition, these patients also had ipsilateral head tilt.

The clinicians conducted a retrospective review of pediatric patients with unilateral congenital ptosis who were undergoing ptosis repair in order to analyze their facial asymmetry. All patients were treated between January 1, 2017, and December 31, 2020. The investigators collected the following data from the medical charts: sex, age, laterality, margin to reflex distance 1, levator function, and surgical intervention.

The investigators described that they used clear preoperative photos in which the patients’ heads were not turned. The landmarks of the periorbital region, midface, and lower face were marked, and measurements between the landmarks were taken. The measurements between the ptotic and non-ptotic sides were compared.

A total of 44 patients were included in the study. Nine of the 44 underwent a Mullerectomy, 15 a levator resection, and 20 a frontalis suspension.

The measurements showed the following significant findings: the side of the face with blepharoptosis often had a smaller margin to reflex distance 1 (p < 0.001), a smaller margin to reflex distance 2 (p < 0.005),a smaller horizontal palpebral fissure (p < 0.05), a shorter midface heightp < 0.001), and a more inferiorly displaced lateral canthus (canthal angle, p < 0.001) compared with the side of the face without ptosis. The mean head tilt in the presence of ptosis on the right side (1.37° right tilt) differed significantly from when ptosis was on the left side (0.85° left tilt; p = 0.04), they reported.

The study concluded that in children with unilateral congenital ptosis, the side of the face with the ptosis was the nondominant side of the face. Patients also had ipsilateral head tilt.

Tenzel PA, Brown K, Zhou B, et al. Facial asymmetry in children with unilateral congenital ptosis. 

2022; published online March 30, 2022; doi: 10.1097/IOP.0000000000002174

Clinicians discover the ptotic facial side of the face was the nondominant side of the face in a recent study.

The effects of unilateral congenital ptosis in a pediatric population

Dr. Jeff Cleland, CEO of Ashvattha, duscusses safety data for an at-home subcutaneous injection option being developed for wet MD, and DME presented during the 2022 ARVO annual meeting, held in Denver, Colorado.

This transcript has been lightly edited for clarity.

®. I'm joined today by Dr. Jeff Cleland, CEO of Ashvattha, who will discuss safety data for an at-home subcutaneous injection option being developed for wet AMD and DME. The anti-VEGF candidate will enter a Phase 2 study later this year. Thanks for joining us, tell us about this project.

Thank you, David, I really appreciate the opportunity to join you today. The thesis behind this project came about by the fact that right now everyone has to get an injection with a needle in the eye that gets treated for many of these retinal diseases. And often that occurs every 6 to 8 weeks. And so it's really a heavy treatment burden, not just on the patients, [but ] many of the physicians that we've talked to are really facing a challenge today, being able to actually treat enough patients because of the heavy treatment burden of having to do this administration. 

We’ve looked at it, even from the early days, and when I worked at Genentech, is there a way we can deliver the drug systemically, and really have the same effect as an injection in the eye without the safety side effects? And so that's been our goal and our challenge with our product.

What we are able to show at this year's ARVO is that we are able to dose very safely a very potent anti-angiogenic agent to patients using a subcutaneous administration. And this allows us then to have at-home use of the product by the patients so they can self-administer. Eventually, we will get to market with an auto injector similar to what they do already with an insulin device or something like that. 

And so it makes it much easier on the patient, also easier on the physician. They still have to routinely go back and obviously be checked by the retina ophthalmologist, but at the same time, they wouldn't have to come back in for regular injections into the eye. 

We think this is going to be a real alleviation of the treatment burden for patients and providers. Many patients over time do get burned out and stop coming back for treatment. So maybe we can save a few patients vision over the long term, as well.

Ultimately, what can this mean for patients?

I think the great advantage of this is that the patients that maybe don't even want to consider a needle in the eye will now have an option that's better, and provides them a chance to continue to maintain their vision and make it easy for them to self-administer at home. 

Eventually, and we're working on this now in the background, as well, a possible oral dosage form of the same product. We can offer patients a pill at some point in the future, instead of having an injection in the eye.

You alluded to it, but what's the next step for this study?

So the next step is that we're about to start enrolling patients and a Phase 2 program. These are wet age related macular degeneration patients and diabetic macular edema patients. They've already been treated with an anti-VEGF previously, and they've shown a response to that, but they have to keep coming back in for those intravitreal injections. And so instead of having their next intravitreal injection, they would come back in and get an injection of Eylea or aflibercept. We'd see how long they respond to that injection. So we have a control baseline. And once they have a return of subretinal fluid back to baseline, they'll get a subcutaneous dose of our drug, and we'll again follow them and see how long they respond and how well they respond to our drugs. 

Each patient becomes their own control in the first part of the study. We think this will be a very powerful study to show that the drug actually does have the potential for therapeutic benefit in these patients.

Thank you so much for taking a little time to catch up again with us and I appreciate it.

Videos

Jeff Cleland, PhD, CEO of Ashvattha, discusses safety data for an at-home subcutaneous injection option being developed for wet AMD and DME. The anti-VEGF candidate will enter a Phase 2 study later this year.

Safety data for at-home subcutaneous injection option for treatment of wet AMD, DME

While there is some value to passive learning from textbooks or online content, retention is better with interaction, reflection and also through experiential learning: doing.

Pupillary examination is obviously central to ophthalmic assessment, but also highly relevant for those managing a range of emergency, neurological and general medical presentations.

While medical students can practice pupillary examinations on each other, they will have normal reactions. Another option is simulated patients, which can be pharmacologically dilated, but they are a limited resource, and no other abnormality can be simulated.

The challenge is for students to have seen a range of pupil abnormalities before they’re in a cubicle with a real patient. So, they are sent to as many clinical settings as possible, sometimes with a logbook, in the hope that they all get enough opportunities to see, and maybe even to examine abnormal pupils. It works generally, but for seeing a range of pupil abnormalities, its opportunistic. One solution seems obvious: virtual reality.

Michael Williams, PhD, School of Medicine, Dentistry and Biomedical Science at Queen’s University of Belfast in Belfast, North Ireland, has worked with a VR coding company to develop an application for pupillary examination.

 Williams noted that the app is developed for the Oculus headsets. The user starts in a clinic reception room, where they select one of 12 different options: 10 different pupil abnormalities (like right APD, left fixed dilated pupil with ptosis, right fixed dilated pupil with red eye etc.), random and normal options.

“Then they enter the clinical room, where the patient awaits with whatever pupil abnormality has been selected,” Williams said in the study. “The user’s point of view can be cast to any device on the same WiFi network. The user picks up a pen torch, turns it on and examines the pupils, using the same physical movements as would be used in real life, swinging the torch between eyes, or moving towards the patient for a closer look for example.”

Williams noted that the VR option has been used with more than 250 final year medical students in Queen’s University of Belfast, as part of a session called “The Simulated Eye Clinic.”

According to the study, most of the students had never used VR prior to the session, and there was often a reaction of pleasant surprise as they put the headset in place and began interacting with a virtual patient.

The pen torch is held and moved as in real life. (Image courtesy of Michael Williams, PhD)

“I learned how to instruct students and get them examining the pupils within 30 seconds to 60 seconds,” Williams wrote. “For example, I learned seemingly obvious things like showing them the only two buttons they would need on the controller before they put the headset on, and going in myself first to choose the pupil abnormality, so the student started in front of the patient. Students worked in pairs, so the first student to do it then taught the second.”

Williams then noted that within 10 minutes per pair, more than 250 students were able to examine an afferent pupillary defect, and a fixed dilated pupil in a red eye, i.e. acute glaucoma. Moreover, when surveyed, 96% of 69 respondents said even this short experience improved their knowledge and confidence of examining pupils.

One student noted that it gave them a chance to see an APD, which they had never seen before. Another said it removed the anxiety out of performing in front of classmates.

Williams noted in the study that VR is a tool, and rather than being enticed by its novelty, it must be used as part of an overall educational strategy, to deliver specific learning outcomes. It has potential use for assessment too.

In the study, Williams also noted that practice continues to be the best way to learn the skill, and hinges on repetition, intentionality, faith and fun.

However, VR can provide a cost-effective option for students to engage in clinically relevant, deliberate practice, with an SP who won’t get tired and will have any abnormality desired.

“Never to be a replacement for learning with real patients, it is a tool to accelerate preparation for meeting real patients,” Williams concluded in the study.

Williams has a commercial interest in the app. No external funding was involved in the development of the app.

Williams, M. Virtual reality in ophthalmology education: simulating pupil examination. 

(2022). https://doi.org/10.1038/s41433-022-02078-3

The challenge is for ophthalmology students to have seen a range of pupil abnormalities before they are in a cubicle with a real patient. One solution to this challenge may be virtual reality.

Virtual reality gives ophthalmology students chance to view pupil abnormalities

Ayette Segrè, PhD, presented her work on trying to understand the biological causes and cell types that lead to one of the leading causes of irreversible blindness worldwide, which is primary open angle glaucoma during the 2022 ARVO annual meeting, held in Denver, Colorado.

I presented work on trying to understand the biological causes and cell types that lead to one of the leading causes of irreversible blindness worldwide, which is primary open angle glaucoma.

It's characterized by gradual retinal ganglion cell death that leads eventually to the degeneration of the optic nerve head and visual field loss and can lead to blindness. And the underlying causes, the genes and processes that lead to the disease, are not very well understood. 

So we use the approach that integrates both very large population-based genetic study that covered over 100 regions in the genome with common DNA changes associated with risk for developing primary open angle glaucoma and integrated that with additional functional genomic information that tells us about what the different DNA changes in the genome do to gene expression, and in which cell types in eye tissues both in the front and back of the eye in which cell types they're expressed. 

By developing a method that integrates both genetic associations from these very large population-based studies, what we call genome wide association studies, together with gene expression in single cells both in tissues in the front of the eye, for example, the outflow pathway through which the aqueous humor flows and it's the blockage of its drainage has been thought to affect and lead to elevated intraocular pressure, which is one of the major risk factors of primary open angle glaucoma, as well as looking at expression in the back of the eye and in the optic nerve head and in the retina and the optic nerve head where the retinal ganglion cell death occurs, and by integrating both pieces of information we found we're able to uncover genes and biological processes we think may be affecting the risk for developing this form of glaucoma. And we found that a lot of the genes tend to be expressed both in the conventional and the unconventional outflow pathway, also genes associated with intraocular pressure, there's a major risk factor.

But also an interesting fact is that about 40% of patients with primary open angle glaucoma have an intraocular pressure in a normal range of pressure. And that suggests that there may also be intraocular pressure independent mechanisms that lead to the degeneration of the optic nerve. And we found that many of the genes that map to the genomic loci associated with risk for developing primary open angle glaucoma, enrich for expression in microglia cell types in the retina and around the optic nerve — so these are cell types that support the metabolic supply and structural support of the retinal ganglion cells that you know that may be affecting itself and ability to survive.

So it suggests that we did not see actually genes enriched for expression in the retinal ganglion cells themselves, suggesting that, you know, thinking about in the future different developing new therapies might be important to think about targeting the neuronal support cells in addition to maintaining the health of the retinal ganglion cells.

The next step we're planning on kind of following up on these results, seeing if they replicate, reproduce in an independent secondary study both of single nucleus RNA-sequencing of additional healthy eye tissues from from donors; as well as in an even larger population-based study looking for genetic risk factors associated with primary open angle glaucoma, that looked at maybe over 10,000 additional cases, and identify now over 300 genomic loci. 

So we're planning on doing this analysis with an even larger set of risk factors for glaucoma together with the single cell data and see if the results stand. And we can learn more about the underlying genes and biological processes. And then down the line we're interested in, in collaborating with experimental biologists here at Mass Eye and Ear to test some of the hypotheses of what genes and pathways may be functioning in particular cell types.

This work suggests that there may be both what is better understood, you know, pathophysiological path that's affecting a risk of POAG through regulation of intraocular pressure, and it's suggesting certain cell types in the front of the eye, some that have been more well established, and others were suggesting particular genes. 

So the hope is, currently there are medications that reduce IOP but my understanding is that some patients they might not be as effective. So having maybe this knowledge of the particular genes that are perturbed and in the particular cell types might help design even better intraocular pressure reducing medications. 

And the other thing is a kind of uncovering the potential role for particular cell types such as the neuronal support cells in the retina and the optic nerve head. This might open a new avenue for developing drugs that will will be helping the neuro protection of the retinal ganglion cells so could open a new avenue for therapies that are for helping treat patients that develop primary open angle glaucoma. And that is not dependent on the intraocular pressure being elevated, but maybe more has to do with the sensitivity of retinal ganglion cells. But that's that's uh, you know, there's work here at Mass Eye and Ear and trying to study the genetic predisposition to what we call normal tension glaucoma.

Presented at ARVO 2022, research from Mass Eye and Ear hopes to open a new avenue for therapies that are for helping treat patients that develop primary open angle glaucoma.

Understanding the biological causes and cell types that lead to one of the leading causes of irreversible blindness worldwide could benefit treatment in patients

Safety data for at-home subcutaneous injection option for treatment of wet AMD, DME

Virtual reality gives ophthalmology students chance to view pupil abnormalities

Understanding the biological causes and cell types that lead to one of the leading causes of irreversible blindness worldwide could benefit treatment in patients

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