In this episode of Retina Mentor Moments, host John W. Kitchens, MD, is joined by Dilsher S. Dhoot, MD, a well-respected retina specialist and researcher who practices at California Retina Consultants (CRC), to discuss the process of going from a retina fellowship to joining a practice and eventually leading clinical trials.
The pair also review how to discuss the results of geographic atrophy (GA) clinical trials with patients when discussing potential treatment options.
From fellowship to joining an ophthalmology practice
After residency, Dr. Dhoot pursued a retina fellowship at the Cleveland Clinic Cole Eye Institute where he was exposed to many career development opportunities because his mentors took him under their wing.
During his fellowship, he met with industry partners, learned about upcoming and ongoing clinical trials, and was introduced to retina specialist key opinion leaders (KOLs). He explained that his mentors helped him lay the groundwork for developing the skills necessary to join and lead an ophthalmology practice.
Choosing your first ophthalmology job after fellowship
Towards the end of his fellowship, Nathan Steinle, MD, a colleague whom Dr. Dhoot met earlier in the fellowship, recruited him to join a practice in Bakersfield, California. Being recruited by a former colleague facilitated the process of vetting the practice, as Dr. Dhoot had an insider’s perspective on the practice workflow, compensation and benefits, and expectations.
While going through this process, Dr. Dhoot consulted one of his mentors at the Cleveland Clinic, Arun Singh, MD, who said, “You have two choices. You can either be the head of a mouse or the tail of a lion. No choice is wrong, you just have to pick.” Meaning, that Dr. Dhoot could either join a larger practice with established KOLs and research or a smaller growing practice. Ultimately, Dr. Dhoot chose to be the tail of a lion, which further propelled his career forward.
Finding your place as a new ophthalmologist in an established practice
One of the challenges many new ophthalmologists face is establishing themselves as thought leaders and researchers while developing relationships with industry contacts, noted Dr. Kitchens. However, Dr. Dhoot began this process during his fellowship at Cleveland Clinic, so by the time he had joined a private practice, people already knew his name and were familiar with his work.
In addition, he explained that the practice partners, Robert “Bob” Avery, MD, and Dante Pieramici, MD, generously gave him the Principal Investigator (PI) title for an investigator-sponsored trial (IST) of high-dose Lucentis (ranibizumab, Genentech) called the REEF study that they had started several years prior to him joining the practice.1
Consequently, Dr. Dhoot led this study comparing the efficacy of 0.5mg and 2.0mg ranibizumab intravitreal injections in patients with diabetic macular edema (DME) refractory to bevacizumab treatment.1 Dr. Dhoot later presented this data at the podium at the American Academy of Ophthalmology (AAO) annual meeting—showing the critical role that mentorship can play in building skills and developing relationships early on in your ophthalmology career.
Identifying high-impact clinical research opportunities
Dr. Dhoot remarked that one of his favorite studies of his career actually took place in 2006 while he was in medical school, around the time that Avastin (bevacizumab, Genentech) was approved by the US Food and Drug Administration (FDA) for intravitreal administration to treat neovascular age-related macular degeneration (nAMD).2
To elucidate the stability of the molecule, Dr. Dhoot—then a student—joined a study led by his mentor Timothy Stout, MD, MBA, PhD, that evaluated the in vitro binding capability of bevacizumab to vascular endothelial growth factor (VEGF) in fresh (aged up to 8 weeks after initial preparation) and freeze/thawed bevacizumab.2 He recounted that they tested the shelf life of bevacizumab by placing syringes in light-protective brown plastic bags at room temperature for 1 week and 8 weeks.2
Additionally, they froze syringes of bevacizumab at -80° Celsius for 20 minutes and thawed them at 25° Celsius for 30 minutes once and three times consecutively in an attempt to destabilize the molecule. They then used enzyme-linked immunosorbent assay (ELISA) kits to measure whether the binding capability of bevacizumab had changed and checked for bacterial contamination.2
They found that bevacizumab was remarkably stable, emphasized Dr. Dhoot, and could effectively bind VEGF up to 8 weeks after preparation, and freeze-thawing the syringes did not hinder its efficacy.2
Discussing GA clinical trial results with patients
Patients have varying levels of motivation and education, noted Dr. Dhoot, so he has found that showing patients their imaging is critical to explaining and helping them understand the progression of geographic atrophy.
Consequently, when discussing GA with patients, the first thing he does is pull up imaging from at least 1 year ago and then compare it to current imaging to highlight the rate of atrophy. He then connects the atrophy seen on imaging to the symptoms reported by the patient to contextualize their complaints within the visual consequences of GA.
Then, Dr. Dhoot mentions that there are two new FDA-approved treatments for GA—intravitreal pegcetacoplan (SYFOVRE, Apellis Pharmaceuticals, Waltham, MA) and avacincaptad pegol (IZERVAY, Astellas Pharma, Tokyo, Japan)—and reviews findings from clinical trials.
Clinical trials on complement inhibitor treatments for GA
Of note, four clinical trials have evaluated the safety and efficacy of pegcetacoplan (OAKS and DERBY) and avacincaptad pegol (GATHER1 and GATHER2). OAKS and DERBY were two multicenter, randomized, double-masked, sham-controlled phase 3 clinical trials that assessed pegcetacoplan administered via intravitreal injections every month or every other month (EOM) respectively in GA patients.3
Similarly, GATHER1 and GATHER2 were randomized, double-masked, and sham-controlled clinical trials that evaluated intravitreal avacincaptad pegol (ACP) at 12 months and 24 months, respectively.4 GATHER2 compared monthly and EOM dosing of ACP 2mg, while GATHER1 looked at monthly dosing of ACP 2mg and ACP 4mg.4
In general, he prefers to mention the 1- and 2-year data from both drugs to set clear treatment expectations that the therapies can slow down the growth of atrophy but cannot reverse or stop disease progression. Subsequently, he mentions the results from the 2- or 3-year studies to highlight the potential long-term benefits.
For example, Apellis Pharmaceuticals released 3-year data from the GALE extension study that suggested in Year 3 pegcetacoplan injection results in:5
- Reduced GA lesion growth (monthly 35% and EOM 24%, p<0.0001) compared to the projected sham arm
- Decreased nonsubfoveal GA lesion growth (monthly 42%, p<0.0001 and EOM 28%, p=0.0015) compared to the projected sham arm
- Reduced GA lesion growth by 19% (p<0.0001) after 1 year of SYFOVRE treatment (combined monthly and EOM) compared to the sham treatment period in patients who crossed over from the sham group
Adverse events associated with GA treatments
He added that it is critical to discuss the safety of the drugs by presenting patients with their side effect profiles. In his professional medical opinion, the most pertinent adverse event to mention is retinal vasculitis, which Apellis has reported to be a rare complication that occurs at 0.01% per injection.6
He also reviewed other potential adverse events with patients, such as choroidal neovascularization (CNV), optic neuropathy, endophthalmitis, and intraocular inflammation (IOI).
Advice for colleagues on the fence about GA treatments
Dr. Dhoot remarked that the clinical trials for pegcetacoplan and ACP have been a learning process, and he personally believes that the investigators did not pick the most appropriate visual endpoints for the patient population.
First, it is difficult to demonstrate visual endpoints in a population that experiences subfoveal atrophy, he explained, and second, post hoc analyses of these trials have indicated that defect-mapping microperimetry is likely the most sensitive way to detect changes in visual sensitivity.7
As future trials are designed, he noted that there will likely be functional visual endpoints that more appropriately measure changes in vision and track the disease process.
What’s to come in the next 5 years for retina specialists?
Dr. Dhoot emphasized that the retina pipeline is filled with exciting new agents to offer patients in the future that will add value in terms of durability, drying ability, and, hopefully, vision—particularly for patients with AMD.
He is particularly excited to see developments in gene therapies and tyrosine kinase inhibitors (TKIs), but other avenues, such as senolytic therapy, also show great potential.8
Final thoughts
To close, the pair briefly discussed their favorite retina conferences; Dr. Dhoot noted that last year, his favorite meeting to attend was Fuji Retina because he enjoyed traveling to Japan.
In terms of domestic conferences, he added that he enjoys going to smaller, more intimate meetings, such as the annual meetings for both The Macula Society and The Retina Society.
Dr. Kitchens remarked that last year, he attended the annual FLORetina meeting in Rome and said that the location was a beautiful backdrop for quality discussions with colleagues.
