An Open-Label Extension Study to Evaluate Safety & Tolerability of QR-421a in Subjects With Retinitis Pigmentosa

PQ-421a-002 is an open-label, extension study to evaluate the safety, tolerability and efficacy of QR-421a (ultevursen) in subjects with RP due to mutations in exon 13 of the USH2A gene.

Subjects that have participated in QR-421a clinical studies, i.e. PQ-421a-001 (Stellar), PQ-421a-003 (Sirius) and PQ-421a-004 (Celeste), will be given the opportunity to enroll into this extension study for continued dosing, provided the subject's benefit-risk assessment is positive, or for additional follow up.

The Investigator, in consultation and agreement with the Medical Monitor, will decide on subject's enrollment upon assessment of subject's benefit-risk.

QR-421a will be first administered to the Contralateral Eye (CE or fellow eye), as defined in the preceding study, and will be repeated every 6 months.

Administration of QR-421a to the Treatment Eye (TE or study eye), as defined in the preceding study, can commence 3 months (9 months for subjects from study PQ-421a-001) after the treatment of the contralateral eye has been initiated and will be repeated every 6 months as well.

The Investigator, in consultation and agreement with the Medical Monitor, will decide on dosing of both eyes. Continued subject treatment in this study will be pursued provided that the benefit-risk balance is positive for the individual subject, as discussed and agreed upon with the Medical Monitor.

The same safety monitoring protocol and efficacy assessments will apply to both eyes.

Baseline functional and structural measurements for the treatment eye will be those from the preceding QR-421a study. Baseline functional and structural measurements for the contralateral eye will be those from the Screening /Day 1 visit of the current study.

• RNA antisense oligonucleotide for intravitreal injection (Drug): QR-421a will be first administered to the fellow eye (as defined in the preceding study), and will be repeated every 6 months. Treatment of the study eye (as defined in the preceding study) can commence 3 months (9 months for subjects from study PQ-421a-001) after the treatment of the fellow eye has been initiated and will be repeated every 6 months as well. Continued subject treatment in this study will be pursued provided that the benefit-risk balance is positive for the individual subject.

Primary outcomes

• Ocular Adverse Events (AEs) [1 year, 1 month]: Number of subjects with ocular treatment emergent adverse events (TEAEs) in the contralateral eye (CE) is presented. Frequency of individual TEAEs by system organ class and preferred term is presented in the safety section and clinical trial summary report. Time frame of reporting is the maximum followup period from first subject first visit to last end of study visit.
• Non-ocular Adverse Events (AEs) [1 year, 1 month]: Number of subjects with non-ocular treatment emergent adverse events (TEAEs) is presented. Frequency of individual TEAEs by system organ class and preferred term is presented in the safety section and clinical trial summary report. Time frame of reporting is the maximum follow up period from first subject first visit to last end of study visit.

Secondary outcomes

• Best Corrected Visual Acuity (BCVA) [24 months]: Change from baseline
• Low Luminance Visual Acuity (LLVA) [24 months]: Change from baseline
• Ellipsoid Zone (EZ) Area/Width by Spectral Domain Optical Coherence Tomography (SD-OCT) [24 months]: Change from baseline
• Static Perimetry [24 months]: Change from baseline
• Microperimetry [24 months]: Change from baseline
• Exposure of QR-421a in Serum [12 months]: Exposure of QR-421a in serum

Sex: All, ages: 12 Years to any

Principal Inclusion Criteria:

1. Subjects who have participated in a preceding QR-421a study and who may derive benefit from continued treatment with QR 421a, and/or continued follow up, as assessed by the Investigator, in consultation and agreement with the Medical Monitor
2. An adult (≥ 18 years) 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.

OR A minor (12 to < 18 years) able to provide age-appropriate assent for study participation, and 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.

Principal Exclusion Criteria:

1. 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 has uncontrolled 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.
2. 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.
3. Safety issue during preceding QR-421a study that may compromise subject safety when continued dosing, as determined by the Investigator, and in consultation with the Medical Monitor.

Participant flow

Outcome results

• Ocular Adverse Events (AEs) (Primary), Count of participants, Participants: Ultevursen 180ug/60ug 11; Ultevursen 60ug/60ug 0
• Non-ocular Adverse Events (AEs) (Primary), Count of participants, Participants: Ultevursen 180ug/60ug 11; Ultevursen 60 ug/60 ug 0
• Best Corrected Visual Acuity (BCVA) (Secondary)
• Low Luminance Visual Acuity (LLVA) (Secondary)
• Ellipsoid Zone (EZ) Area/Width by Spectral Domain Optical Coherence Tomography (SD-OCT) (Secondary)
• Static Perimetry (Secondary)
• Microperimetry (Secondary)
• Exposure of QR-421a in Serum (Secondary)

Adverse events

Time frame: 1 year,1 month

Other adverse events by term

Limitations and caveats: Study prematurely terminated due to sponsor decision for reasons unrelated to safety.

• Study Protocol (PDF, 2022-05-24)
• Statistical Analysis Plan (PDF, 2022-10-19)

• Sepul Bio Medical Monitor, Study director, Sepul Bio