Author: Birgit Lorenz (Germany)
Co-authors: Joana Tavares, L Ingeborgh van den Born, João P Marques, Hendrik P N Scholl, The EVICR.net Group The EVICR.net Group
US FDA in 2017 and EMA Europe in 2018 have approved the first ocular gene augmentation therapy, voretigene neparvovec VN, for clinical use. Since then, many more countries worldwide have followed. Among the EVICR.net clinical centers, we conducted the first multinational survey to understand distribution, diagnostic work-up, and management of inherited retinal degenerations (IRD) cases in Europe with a special focus on RPE65 mutation-associated IRDs.
All 101 EVICR.net clinical centers during May and June 2019.
An electronic survey questionnaire including 35 questions specifically addressing RPE65 mutation-associated IRDs was sent to the responsible person of the Clinical Center and to its representative for the EVICR.net Retinal Dystrophies Scientific Section of the 101 EVICR.net clinical centers. Only one reply per Clinical Center was considered for analysis. A reminder was sent to the non-repliers after 2 weeks, the deadline was extended by 2 weeks and new reminders were sent on week 3 and 4. The questionnaire comprised five sections: Section 1: IRD demographics, Section 2: Local setting, Section 3: IRD Genetic testing and counselling, Section 4: Involvement in Clinical Trials and Section 5: RPE65 mutation-associated IRDs. The results from Sections 1 to 4 were reported separately. We conducted a descriptive analysis to all variables. Continuous variables were summarized using the following statistics: number (n), mean, standard deviation (SD), median (P50), first and third quartiles (P25 and P75), minimum (Min) and maximum (Max). The frequency and percentages of observed levels were reported for all categorical measures. For statistical analyses, we used Excel version 15.0.4433.1508 (Microsoft Office Home and Business 2013) and R version 3.6.0 (2019-04-26).
The overall response rate was 49%. Forty-two centers see IRD patients, and 22/42 follow patients with confirmed biallelic RPE65 mutations. Fifteen of the 22 centers (68%) and 3/22 (14%) follow 1-5 and 6-10 patients with homozygous RPE65 mutations, respectively. Additionally, 15/22 (68%) and 3/22 (14%) follow 1-5 and >20 patients with compound heterozygous RPE65 mutations, respectively. Fifty-nine percent of mutations were American College of Medical Genetics (ACMG) Class 4 and 5 (at least one allele), 82.8% had been reported previously and 17.2% were novel. Referral diagnoses (mean per center) were Leber Congenital Amaurosis (38.2%), Early-onset severe retinal degeneration (16.8%), Rod-Cone-Dystrophy/Retinitis pigmentosa (RP) (28.1%), and unclassified visual impairment (17.0%). Twenty-five percent of the centers changed the referral diagnosis in 48% of cases; 32% follow a specific referral process for RPE65 mutation-associated IRD patients. Annual follow-up visits are done in 55% of the centers, and biannual visits in 23%. In 32%, other centers also follow the patients. Kinetic perimetry is done in 82%, static perimetry in 45%, microperimetry in 18% of the centers, chromatic Full-field Stimulus Test (FST) to quantify rod and cone function is used in 6/22 centers (27%). A mobility course is available in one center (5%).
This first multinational survey on management of patients with RPE65 mutation-associated IRDs in Europe shows that about half of the responding EVICR.net centers have such patients under care. There is heterogeneity in diagnoses and management practices. At the start of clinical practice experience with voretigene neparvovec, these data provide a useful baseline and highlight the need for consensus/guidelines to inform standard of care in this new era of gene therapy.
Novartis Pharma AG through a Scientific Collaboration Agreement between Novartis and AIBILI, the Coordinating Center of EVICR.net funded this study. Novartis provided non-binding comment/input to the IRD Survey Expert Committee into all elements of the scientific collaboration agreement. Dr. Birgit Lorenz: paid talks or consultant for: Novartis GmbH (RPE65) and Janssen Global Services, LLC (XLRP). Dr. Hendrik Scholl is supported by the Swiss National Science Foundation, National Center of Competence in Research Molecular Systems Engineering; the Wellcome Trust; the Translational Research Acceleration Program Award by the Foundation Fighting Blindness (FFB); and the FFB Clinical Research Institute. Dr. Hendrik Scholl is member of the Scientific Advisory Board of: Apellis Switzerland GmbH, ARCTOS medical AG; Astellas Pharma Global Development, Inc./Astellas Institute for Regenerative Medicine; Biogen MA Inc.; Boehringer Ingelheim Pharma GmbH & Co; Gyroscope Therapeutics Ltd.; Janssen Research & Development, LLC (Johnson & Johnson); Novartis Pharma AG (CORE); Okuvision GmbH; Pharma Research & Early Development (pRED) of F. Hoffmann-La Roche Ltd; ReVision Therapeutics, Inc.; and Stargazer Pharmaceuticals, Inc. Dr. Scholl is a paid consultant of: Gerson Lehrman Group; Guidepoint Global, LLC; Tenpoint Therapeutics Limited; and Third Rock Ventures, LLC.