study to evaluate safety and tolerability of qr-421a in subjects with rp due to mutations in exon 13 of the ush2a gene

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

Summary: the purpose of this study is to evaluate the safety and tolerability of qr-421a administered via intravitreal injection (ivt) in subjects with retinitis pigmentosa (rp) due to mutations in exon 13 of the ush2a gene.

the purpose of this study is to evaluate the safety and tolerability of qr-421a administered via ivt in subjects with rp due to mutations in exon 13 of the ush2a gene. subjects will receive one single ivt injection of qr-421a or sham-procedure in one eye (subject's worse eye) and will be followed up for 24 months. three dose levels of qr-421a will be evaluated: 50, 100, and 200 µg. additional dose levels (eg, 25 or 400 µg) may be evaluated based on ongoing safety and efficacy data monitoring. initial dose cohorts will include subjects randomized to sham-procedure or treatment with qr-421a. additional subjects may be allocated to treatment with qr-421a in subsequent or initial dose cohorts.

Eligibility criteria:
inclusion criteria: 1. male or female, ≥ 18 years of age. 2. clinical presentation consistent with rp with usher syndrome type 2 or non-syndromic rp (nsrp), based on ophthalmic, audiologic, and vestibular examinations. 3. a molecular diagnosis of homozygosity or compound heterozygosity for 1 or more pathogenic exon 13 mutations in the ush2a gene, based on genetic analysis upon sponsor approval. 4. impairment of vf in the opinion of the investigator, as determined by perimetry, with a continuous area of central field greater than or equal to 10 degrees diameter in any axis in the treatment eye, and evidence of functioning rods. 5. willing and able to comply with the protocol, follow study instructions, attend study visits as required and complete all study assessments. 6. willing and able to provide informed consent for participation prior to performing any study related procedures, and suitable verbal, auditory, written and/or tactile sign language communication as to allow informed consent to be obtained, in the opinion of the investigator. 7. no limitations to sd-oct image collection that would prevent high quality, reliable images from being obtained in both eyes as determined by the investigator. 8. reliable perimetry measurements in both eyes, as described in the imaging manual and determined by the investigator. 9. clear ocular media and adequate pupillary dilation to permit good quality retinal imaging, as assessed by the investigator. exclusion criteria: 1. presence of additional non-exon 13 ush2a pathogenic mutation(s) on the ush2a allele carrying the exon 13 mutation in subjects who are compound heterozygous for mutations in exon 13. 2. presence of non-exon 13 ush2a pathogenic mutation(s) on both ush2a alleles in subjects who are homozygous for mutations in exon 13. 3. presence of pathogenic mutations in genes (other than the ush2a gene) associated with usher syndrome type 2 or nsrp, or other inherited retinal degenerative diseases or syndromes. 4. presence of any significant ocular or non-ocular disease/disorder (or medication and/or 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 influence the results of the study, or the subject's ability to participate in the study. this includes but is not limited to a subject who: 1) is not an appropriate candidate for antisense oligonucleotide treatment, 2) has cystoid macular edema (cme) in the treatment eye. cme is permissible if stable for 3 months (with or without treatment). past cme is permissible if resolved for more than 1 month. 5. history or presence of ocular herpetic diseases (including herpes simplex virus, varicella zoster or cytomegalovirus) in either eye. 6. presence of any active ocular infection in either eye. 7. presence of any of the following lens opacities in the treatment eye: cortical opacity ≥ +2, posterior subcapsular opacity ≥ +2, or a nuclear sclerosis ≥ +2, and which are: 1) clinically significant in the opinion of the investigator, 2) would adequately prevent clinical and photographic evaluation of the retina. 8. history of amblyopia in the treatment eye. 9. worse than 6 diopters myopia in the treatment eye. 10. receipt within 3 months prior to screening of any intraocular or periocular surgery (including refractive surgery), or an ivt injection or planned intraocular surgery or procedure during the course of the study. 11. current treatment or treatment within the past 12 months with therapies known to influence the immune system (including but not limited to steroid implants, cytostatics, interferons, tumor necrosis factor (tnf)-binding proteins, drugs acting on immunophilins, or antibodies with known impact on the immune system). subjects that have been treated with systemic steroids within the past 12 months or that require intermittent use of topical steroids may be considered for inclusion following approval by the medical monitor. 12. a history of glaucoma or an iop greater than 24 mmhg in either eye that is not controlled with medication or surgery at the time of informed consent. 13. use of any investigational drug or device within 90 days or 5 half-lives preceding the first dose of study medication, whichever is longer, or plans to participate in another study of an investigational drug or device during the pq-421a-001 study period. 14. any prior treatment with genetic or stem-cell therapy for ocular or non-ocular disease. 15. history of malignancy within 5 years prior to screening, except adequately treated squamous or basal cell carcinoma of the skin or carcinoma in situ of the cervix that has been successfully treated. 16. known hypersensitivity to antisense oligonucleotides or any constituents of the injection. 17. pregnant and breastfeeding subjects. females of childbearing potential and males must comply with using highly effective methods of contraception as defined in section 6.2.2. women of non-childbearing potential may be included without the use of adequate birth control, provided they meet the criteria in the protocol.

Keywords: retinitis pigmentosa ush2a rp exon 13 rna therapies antisense oligonucleotide exon skipping stellar ivt mutations in exon 13 of the ush2a gene nsrp