study to evaluate ultevursen in subjects with retinitis pigmentosa (rp) due to mutations in exon 13 of the ush2a gene

Conditions: Retinitis Pigmentosa (RP); Usher Syndrome Type 2; Deaf Blind; Retinal Disease; Eye Diseases, Hereditary; Eye Disorders Congenital; Vision Disorders

Summary: the purpose of this phase 2b study is to evaluate the safety and tolerability of ultevursen administered via intravitreal injection (ivt) in subjects with retinitis pigmentosa (rp) due to mutations in exon 13 of the ush2a gene. this is a multicenter double-masked, randomized, sham-controlled study which will enroll 81 subjects.

a total of eighty-one (81) rp participants will be enrolled in this study, randomized in a 2:1 ratio to either ultevursen or sham procedure, respectively. subjects randomized to the active treatment group will receive therapy with ultevursen administered via intravitreal (ivt) injection to the treatment eye (te) on day 1 and at months 6, 12, and 18. subjects randomized to sham will undergo a sham procedure in the te at the corresponding timepoints.

Eligibility criteria:
inclusion criteria: 1. an adult (≥18 years) willing and able to provide informed consent for participation prior to performing any study related procedures or a minor (8 to less than 18 years) able to provide age-appropriate assent for study participation with a parent or legal guardian willing and able to provide written permission for the subject's participation prior to performing any study related procedures. 2. both eyes exhibit clinical presentation consistent with rp involving usher syndrome type 2 or nsrp based on ophthalmic, audiologic, or vestibular examinations. at screening, the investigator will make the clinical diagnosis of "usher syndrome type 2a," defined as rp with congenital hearing loss, or "non-syndromic rp," defined as rp without congenital hearing loss. 3. a molecular diagnosis of biallelic disease causing variants (pathogenic or likely pathogenic) in the ush2a gene where at least one of the variants is located on exon 13. a historic genotyping report from a certified laboratory is acceptable with sponsor approval. 4. clearly visible and measurable ez width of ≥2.5 mm in both horizontal and vertical scans in both eyes as measured by sd-oct and based on the assessment of the crc. 5. bcva ≥55 letters based on etdrs (equivalent to 20/80 based on snellen notation, or logarithm of the minimum angle of resolution \[logmar\] +0.6) in both eyes. 6. impairment of vf as assessed by sp with a mean sensitivity greater than 4 decibels (db) and less than 25 db measured by a v4e target size in the te. 7. mean sensitivity greater than 2 db as determined by mp in the te. 8. symmetry of baseline disease in both eyes, defined as the mean bcva (based on etdrs) of one eye within ≤10 letters of the mean bcva of the other eye at screening. if this is not present, the investigator should discuss the case with the medical monitor to decide whether it is appropriate for the subject to participate in the study. for purposes of determining symmetry, the mean bcva for each eye will be calculated using all bcva measures obtained during the screening period. exclusion criteria: 1. presence of additional non-exon 13 ush2a pathogenic or likely pathogenic variant on the ush2a allele carrying the exon 13 mutation in subjects who have one exon 13 disease causing variant and one non-exon 13 disease causing variant. 2. presence of additional non-exon 13 ush2a pathogenic mutation(s) on both ush2a alleles in subjects who have biallelic exon 13 mutations. 3. presence of pathogenic or likely pathogenic variants in genes (other than the ush2a gene) which are known to be associated with other inherited retinal degenerative diseases or syndromes. specifically, the presence of homozygous or compound heterozygous known disease-causing mutations in other genes involved in recessive retinal dystrophies, or the confirmed presence of a known single disease-causing variant in genes involved in dominant, x-linked, or mitochondrial retinal dystrophy genes is exclusionary. 4. at screening, the ez horizontal or vertical width are outside the field of the sd-oct scan based on the assessment of the crc. 5. presence of any significant ocular or non-ocular disease/disorder (including medication and laboratory test abnormalities) which, in the opinion of the investigator and with concurrence of the medical monitor, may either put the subject at risk because of participation in the study, may impact the subject's ability to participate in the study, or may interfere with assessment of efficacy and safety in the study. 6. presence of unstable concurrent cystoid macular edema (cme), or subject started on (or changed dose of) topical or systemic carbonic anhydrase inhibitor treatment in the 3 months prior to enrollment. cme is allowed if stable for 3 months (with or without treatment). however, stable cme that disrupts the ez width measurement, as determined by crc, is an exclusion. 7. receipt of any prior intraocular or periocular surgery or planned intraocular surgery or procedure during the study. subjects may be considered for inclusion if there are no clinically significant complications of surgery present and following approval by the medical monitor. 8. receipt of any ivt injection prior to study entry. however, subjects who have received a prior ivt injection may be considered for inclusion following approval by the medical monitor.

Keywords: retinitis pigmentosa usher syndrome type 2 deaf blind ush2a rp exon 13 rna therapies antisense oligonucleotide exon skipping luna ivt nsrp