Retina Therapeutic Roundup

Recent therapeutic advances in the management of retinal disease (Figures 1 and 2) continue to uncover new treatment targets and provide additional management options. This article reviews some of the current investigational therapeutics that have the potential to profoundly affect the management of such diseases, with a focus on first-in-class drug candidates.

TREATMENTS THAT TARGET GEOGRAPHIC ATROPHY

Geographic atrophy (GA) due to dry age-related macular degeneration (AMD) represents the accumulation of intrinsic stressors affected by external factors that lead to inflammation through the activation of multiple pathways, including the complement cascade.¹ The goal of treating GA with therapeutics that act within the complement system is to reduce the overactivity of the system and to slow, rather than reverse, disease progression. It’s important to remember that GA doesn’t improve. Thus, the goal of treatment is to slow GA growth over time. Therapeutic candidates that target molecules within the complement system support the pathway as an effective location for disease modification.

Pegcetacoplan

Pegcetacoplan (Apellis Pharmaceuticals) is under review by the FDA for the treatment of GA secondary to dry AMD with a Prescription Drug User Fee Act (PDUFA) action date of February 2023.² The New Drug Application (NDA) submission data were based on the phase 2 FILLY trial and the phase 3 DERBY and OAKS trials.

In FILLY, a dose-dependent reduction in the rate of growth of GA lesions with intravitreal injection of pegcetacoplan was observed. Also clinically relevant, in a post-hoc analysis of eyes with incomplete retinal pigment epithelium (RPE) and outer retinal atrophy without choroidal neovascularization (CNV), monthly dosing of pegcetacoplan reduced the rate of progression to complete RPE and outer retinal atrophy by 39% at 12 months versus sham.³ These results show that the process that leads to GA expansion is the same process that drives GA formation, supporting complement overactivation in the pathogenesis of drusen formation.

An interesting safety signal was first identified in FILLY and then in DERBY and OAKS. Although neovascularization in patients with GA is an expected phenomenon and an important feature to watch for clinically, patients converted to neovascular AMD (nAMD) in the treatment arm more frequently than in the sham arm of each trial.^2,4 The recently released 24-month FILLY and OAKS data identified a 12.2% rate of conversion to nAMD in the monthly dosing group versus 6.7% in the every-other-month group, and 3.1% in the sham group.² Importantly, the rates of infectious endophthalmitis and intraocular inflammation were similar to other intravitreal therapies, and no events of retinal vein occlusion or retinal vasculitis were observed.²

The phase 3 OAKS trial met its primary endpoints, with a 21% reduction in the rate of GA growth in the monthly dosing group and a 16% reduction in the every-other-month dosing group versus sham.⁴ However, DERBY just missed its prespecified endpoints, with the monthly dosing group exhibiting a 12% reduction in GA growth (P = .0609) and the every-other-month dosing group exhibiting an 11% reduction in growth rate (P = .0853) versus sham.⁴ When the data from both phase 3 trials were pooled, there was an identified slowing of GA growth rate over time, demonstrating a potential for improving effect of treatment over time.²

With two positive trials and one that just missed statistical significance, the upcoming regulatory action date regarding pegcetacoplan is highly anticipated.

Avacincaptad Pegol

Avacincaptad pegol (Zimura, Iveric bio) targets and inhibits C5 convertase within the complement system and recently met its prespecified endpoint with 14.3% reduction in mean rate of growth in GA over 12 months across two phase 3 clinical trials, GATHER1 and GATHER2.⁵ Similar to clinical trials investigating pegcetacoplan, there was an observed increased incidence of CNV in the treatment group versus the sham group (9.0% vs. 2.7% and 6.7% vs. 4.1%) in GATHER1 and GATHER2 through 12 months.⁵

Geographic differences in treatment effect were observed, with patients in the United States exhibiting a greater reduction in mean rate of growth in GA versus those outside of the United States, which included patients in Croatia, Czechia, Estonia, Hungary, Israel, and Latvia.⁶ The differences in treatment effect have been hypothesized to be related to earlier disease stage and smaller baseline GA area of patients in the United States, identifying a key challenge previously observed in the evaluation of therapeutic candidate effectiveness for GA: Treatments provided too late in the disease course may otherwise be effective if provided earlier in the disease process.⁵ With two positive phase 3 trial results, the first part of the NDA has been submitted to the FDA for rolling review.⁵

Elamipretide

Elamipretide (Stealth BioTherapeutics) is also being investigated as a therapeutic in GA. When injected subcutaneously once daily, the molecule acts to protect mitochondria by reducing the release of reactive oxygen species and by stabilizing mitochondrial structure.⁷ The phase 2 ReCLAIM-2 trial did not meet prespecified primary endpoints of mean change in low luminance visual acuity and GA progression. However, identified preserved ellipsoid zone in the treatment group versus the sham group shows proof of concept of the molecule’s effect.⁷

JNJ-1887

An investigational gene therapy product for GA, JNJ-1887 (Janssen), met its primary endpoints for safety and tolerability in a phase 1 study over a 2-year follow-up period.⁸ JNJ-1887 increases the expression of a soluble form of CD59, which prevents the formation of the membrane attack complex—the final step of the complement pathway that leads to cell death. GA lesion growth rate was also observed to decline throughout the 2-year study period.⁸ Positive phase 1 results support its continuing clinical investigation.

THERAPIES AIMED AT AMD AND MORE

Although existing intravitreal anti-VEGF therapies have shown remarkable success in improving outcomes of patients with retinal vascular disease, the challenges related to treatment burden continue to mount. Investigational therapeutics for the treatment of nAMD, diabetic retinopathy, and macular edema after retinal vascular occlusion aim to reduce treatment burden through the use of agents with increased durability, alternative modes of administration, and gene therapy-based treatments.

OTX-TKI

Tyrosine kinase inhibitors are intracellular small molecules that act to prevent downstream activation of tyrosine kinase cascades, including VEGF and platelet-derived growth factor.⁹ OTX-TKI (Ocular Therapeutix) is a resorbable, intravitreal implant in a phase 1 clinical trial investigating its safety, tolerability, and efficacy in patients with nAMD in the United States, where interim 7-month data identified that 80% of participants were rescue-free up to 6 months after one implant injection.⁹

Ixoberogene Soroparvovec

The phase 2 LUNA study evaluating two concentrations of ixoberogene soroparvovec (Ixo-vec; Adverum Biotechnologies), an intravitreal gene therapy candidate for nAMD and associated prophylactic steroid regimens, is underway.¹⁰ Positive data from the phase 1 OPTIC trial identified that intravitreal aflibercept coding sequence, carried by a proprietary vector capsid injected intravitreally, shows stable aflibercept protein expression through 2 years after a single injection.¹¹ From a safety perspective, no instances of endophthalmitis, vascular occlusions, or vasculitis were identified, with the injection reported to be well-tolerated with dose-dependent inflammation responsive to steroid therapy.¹¹

APX3330

The phase 2b ZETA-1 trial investigating oral APX3330 (Ocuphire Pharma) for the treatment of diabetic retinopathy and diabetic macular edema has recently been completed, and although readout is anticipated by the end of 2022, previously reported safety data demonstrate no evidence of cardiovascular pathology, renal dysfunction, or arteriothrombotic events, with two of 35 participants withdrawing from the trial.^12,13 APX3330 inhibits reduction-oxidation effector factor-1, which blocks downstream VEGF and inflammatory pathways when administered twice daily orally.^12,13

ADX-2191

Also of note is intravitreal methotrexate 0.8% (ADX-2191, Aldeyra Therapeutics), which met its prespecified primary endpoints in part one of the phase 3 GUARD trial for the prevention of proliferative vitreoretinopathy, the most common cause of retinal detachment repair failure.¹⁴ Patients received 13 injections over 16 weeks following pars plana vitrectomy for recurrent retinal detachment.¹⁵ No significant safety signals were identified, and the treatment was well-tolerated.¹⁴

BOTTOM LINE

Topline efficacy data from clinical trials may make headlines, but the only way to truly understand how these results might inform the clinical care of our patients is to dig deeper into the evidence. Evaluating the study population to determine how similar the trial participants are to your patient base can inform how applicable the results are to your clinical practice. Investigating secondary outcome measures can provide insight into how one drug may perform or compare to another. Complete safety data for a product, while readily available, may be reported separately as part of the external or supplemental materials, requiring an extra step to access.

Finally, investigating the study design offers us an understanding of how practical and applicable a product may be in clinical practice. Evaluating clinical trial data for retinal pharmacotherapies is of particular importance, considering the patent expirations for ranibizumab (Lucentis, Genentech) and bevacizumab (Avastin, Genentech) and the upcoming patent expiration for aflibercept (Eylea, Regeneron), which have opened the door for biosimilar agents in the United States. Trials investigating the efficacy of products in comparison to the reference product may not always provide direct clinical context.

The therapeutic development of agents used to treat and manage retinal disease is continuing to expand. Investigational products using alternative mechanisms and routes of delivery aim to improve durability and introduce first-in-class therapy that provides options for retinal disease previously considered untreatable.