BACKGROUND
Inherited retinal diseases (IRDs) are a heterogenous group of conditions that could progress to vision loss and death [1]. There are over 300 genes and loci that have been identified as the cause of IRDs [2]. IRDs impact approximately 2 million people in the world and has a global incidence of 1 in 2000-3000 [3]. Confirmation of the genetic cause of an IRD helps patients receive a concrete diagnosis, which can also lead to therapeutic development for their gene defects (3). Gene therapy and gene-editing approaches may help many patients with IRDs [3]. Efforts to develop gene-based treatments have been underway for more than three decades. In 2017, the U.S. Food and Drug Administration (FDA) approved voretigene neparvovec-ryzl [Luxturna] for Leber Congenital Amaurosis [LCA], which is the first in vivo gene therapy to receive approval [4]. Since then, two other gene therapies have obtained FDA Regenerative Medicine Advanced Therapy [RMAT] designations for IRDs, including JCell for retinitis pigmentosa (RP) and NSR-REP1 for choroideremia [4]. Currently, there are more than 30 clinical trials for gene therapies for IRDs [4]. Patients living with IRDs may experience partial to complete vision loss [5, 6]. Treatments that are available to patients only slow down the progression of disease, if provided early in disease progression [5]. Clinical and subclinical inflammation is also commonly associated with ocular gene therapy for IRDs; the degree of inflammation is correlated with dose; and severe inflammation has been associated with reduced gene therapy efficacy [2]. The quality of life for patients living with IRDs may be severely affected by these effects, which highlights the current unmet medical need in the ocular diseases field [5].
Another common cause of vision loss and blindness is macular degeneration [7]. Over time, macular degeneration results in a decrease in vision sharpness due to “pigmentary and atrophic” alterations in the macula [8]. It has been predicted that the number of patients living with macular degeneration will be approximately 288 million by 2040 [8]. There are two types of age-related macular degeneration (AMD); wet and dry AMD. Neovascular, or wet AMD, patients have access to effective therapy, although some patients do not respond well to treatment [9]. Neovascular AMD patients may have to receive intravitreal injections, such as anti-VEGF (vascular endothelial growth factor) therapy every month for 10 years or longer, which is currently the standard of care for the disorder [10, 11]. Due to the invasiveness and frequency of anti-VEGF therapy, the quality of life of patients and their caregivers may be impacted significantly [11, 12]. Low adherence, as well as significant societal and economic costs, also contribute to the burden of this current treatment approach, which highlights the need for longlasting and less invasive treatment approaches for neovascular AMD [13].
Patients living with non-neovascular AMD, or dry AMD, currently do not have an effective treatment option available to prevent the progression of disease or restore vision loss [9]. Dry AMD is managed through observation and regular follow-up evaluations and documentations for recognition of visual function deterioration [14]. Fortunately, there are numerous treatment options underway; several are in, or have completed, phase 2 and 3 clinical trials [9]. However, the pathogenesis for dry AMD is not completely understood and continues to evolve. This poses an enormous challenge for drug development to identify which factors to target given the multifactorial nature of the disease [14]. Furthermore, disease progression of non-neovascular AMD is slow, which leads to longer follow-up period of clinical trial participants and higher cost. This highlights the need for surrogate clinical endpoints that are acceptable by regulatory standards [15]. Additionally, patients living with AMD can further develop geographic atrophy characterized by progressive and irreversible loss of function [16]. This is defined by the presence of lesions on the outer retina as a result of the loss of important retinal factors, such as photoreceptors [16]. Although there is interpatient variability in the progression rates of geographic atrophy, several therapeutic agents are being investigated in clinical trials [16]. However, there is no standardized rating scale to assess the severity of this disease in a patient to track progression [16]. There are also types of juvenile-onset macular degeneration, which include Stargardt disease, Best disease, retinitis pigmentosa, X-linked retinoschisis, and other associated dystrophies [17]. No cure exists for juvenile macular degeneration, but there are ongoing gene therapy clinical trials for these disorders, as well [18].
Read more about The Forum for Collaborative Research's history, achievements, operating procedures and working process.
THE OCULAR DISEASES FORUM
There are many challenges in the ocular diseases field, including the identification and validation of outcome measures such as biomarkers and endpoints. For many IRDs, treatments may only stabilize or slow down the progression of disease; thus, selecting the method of measuring a treatment benefit for IRDs is critically important [21]. “For use as endpoints in clinical trials, outcome measures should be easy to obtain, highly repeatable and reproducible with minimal measurement or ascertainment error, possible to observe independent of treatment assignment, clinically relevant, and chosen before the start of data collection [21, 22].” New outcome measures that could be utilized include patient-reported outcomes (PROs) that test visual function and performance-based tests (PBTs) that utilize approaches recommended by the FDA [21].
Designing clinical trials for IRDs also pose significant challenges, particularly because there are many gene defects, many mutations for each gene, and the mechanism of action varies. Additional clinical trial design challenges include a small number of participants, cost, and a need for training IRD specialists globally as treatments become available [21].
AIM
The Ocular Diseases Forum aims to advance the regulatory sciences for the treatment of inherited retinal diseases and macular degeneration by providing an independent and neutral venue for ongoing multi-stakeholder dialogue. Our work facilitates making the best science-based decisions as our collective knowledge and experience with therapies for inherited retinal diseases and macular degeneration advances. Once new drug candidates and therapeutic strategies are identified, their rapid and safe development is in the best interest of all stakeholders, and most of all, the patients [23]. The Ocular Diseases Forum provides a platform for careful and ongoing deliberation on issues of common interest and concern. Neutrality and objectivity are ensured through representation and active engagement of scientific experts from all stakeholder groups, including academia, industry, professional societies, patient representatives, payors, and regulatory agencies in a non-competitive and safe environment. This structure allows the whole field to benefit from valuable lessons learned, and breaks down inefficiencies by increasing clarity and standardization, and decreasing uncertainty.
LEADERSHIP
The Ocular Diseases Forum is led by a Steering Committee (SC) and managed by Forum staff. The SC provides overall scientific leadership. The Ocular Diseases Forum agenda is informed by member feedback and determined by the SC. Throughout the year, it is expected that the Ocular Diseases Forum convenes working group conference calls, email/web-based communication, virtual and in-person meetings, webinars, and workshops as needed. This includes identification of individuals with expertise from various stakeholder groups in the Ocular Diseases Forum focus areas.
MEMBERSHIP
Ocular Diseases Forum membership is by invitation only. Project members are recruited from all stakeholder groups, including: academia, industry, professional societies, patient representatives, payors, regulatory agencies and other relevant entities. Industry membership is open to scientific experts from pharmaceutical, biotech, and diagnostic organizations committed to and actively engaged in research and development of therapies for inherited retinal diseases and macular degeneration. Participation from industry is conditional on an annual sponsorship contribution. Guidelines for providing an appropriate contribution are based on company size, market cap, and development status. Industry members are acknowledged as Ocular Diseases Forum sponsors. Sponsorship includes participation in in-person meetings, working groups, workshops, webinars, remote attendance, and project updates. Non-sponsoring industry has access to information published on the Forum’s website. Industry members join as an organization. Commercial, marketing, and investment experts are not permitted to attend closed Ocular Diseases Forum members meetings but will be allowed to participate in any public meetings the Forum sponsors.
Annual contributions from non-industry organizations are encouraged. The Forum does not cover any honoraria or provide items of value (gifts) to any speakers or attendees. Sponsorship cannot be combined/divided for participation in different disease specific projects at the Forum.
References
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