Abstract
Purpose : There are no therapeutic options for Retinitis Pigmentosa type 11 (RP11), a blinding inherited retinal disease caused by haploinsufficiency of the PRPF31 (pre-mRNA processing factor 31) gene. VP-001 has been developed to upregulate PRPF31 protein by downregulating CNOT3 protein expression. CNOT3 negatively regulates PRPF31 by interacting with the PRPF31 promoter region. VP-001 successfully downregulated CNOT3 protein by skipping exon 17 of CNOT-3 pre-mRNA, and upregulated PRPF31 gene expression and the protein in patient derived cellular models. No observed adverse effect level (NOAEL) of VP-001 was established in rabbits and monkeys. Subsequently, a single ascending dose first in human study was started to evaluate initial safety and tolerability of VP-001.
Methods : An open-label, single ascending dose study, recruited participants with genetically confirmed PRPF31 mutation in 3 cohorts. Study eyes received an intravitreal injection of VP-001 (3 µg, 10 µg, 30 µg) and are then followed for 24-week and 48-week time period for incidence, severity and relatedness of ocular treatment-emergent adverse events and treatment-emergent serious adverse events. Three subjects are enrolled for each cohort, and the dose escalation is based on review by a safety review committee (SRC) using 4-week and incremental data collected after each cohort dosing. Safety and tolerability are evaluated based on adverse event (ocular and non-ocular) reporting, that includes clinical chemistry parameters, best corrected visual acuity, perimetry, microperimetry, slit lamp and fundus examination, fundus autofluorescence imaging, and spectral-domain optical coherence tomography.
Results : Six participants (3 µg and 10 µg cohorts) were enrolled till date. No drug related adverse events and no intraocular inflammation were observed at 4 weeks for 10 µg cohort, and at 4 weeks and 12 weeks for 3 µg cohort. Third cohort will receive 30 µg dose, and the safety data collected at day 2, day 14 and week 4 will be reviewed by the SRC. Safety of all the participants will be followed for 24 and 48 weeks.
Conclusions : A single intravitreal injection of VP-001 was safe and well tolerated at 3 µg and 10 µg doses. A 30-µg dose is also administered, and if shown safe at week 4, a 75-µg dose cohort may be added to the study based on recommendation by the SRC. Data from all 3 cohorts will be presented.