Study to Evaluate the Efficacy Safety and Tolerability of Ultevursen in Subjects With RP Due to Mutations in Exon 13 of the USH2A Gene (Sirius)

A Double-Masked, Randomized, Controlled, Multiple-Dose Study to Evaluate the Efficacy, Safety and Tolerability of Ultevursen in Subjects With Retinitis Pigmentosa (RP) Due to Mutations in Exon 13 of the USH2A Gene (Sirius)

The purpose of this study is to evaluate the efficacy 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.

Study Overview

• Status: Active, not recruiting
• Conditions: Eye Diseases; Retinitis Pigmentosa; Eye Diseases, Hereditary; Vision Disorders; Retinal Disease; Eye Disorders Congenital; Usher Syndrome Type 2; Deaf Blind
• Intervention / Treatment: Other: Sham-procedure; Drug: Ultevursen

Detailed Description

The purpose of this study is to evaluate the efficacy 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.

The below dose levels of ultevursen will be evaluated with the loading dose administered at Day 1 and maintenance dose administered at Month 3 and every 6 months thereafter:

1. Loading dose of 180 µg, maintenance dose of 60 µg
2. Loading dose of 60 µg, maintenance dose of 60 µg

Dose levels will include subjects randomized to sham-procedure or treatment with ultevursen.

• Study Type: Interventional
• Enrollment (Anticipated): 81
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• Germany
  • Tuebingen, Germany, 72076
    • Universitaetsklinikum Tuebingen Department für Augenheilkunde
• Netherlands
  • Nijmegen, Netherlands, 6525 GA
    • Radboudumc
  • Rotterdam, Netherlands, 3011 BH
    • Het Oogziekenhuis Rotterdam
• United Kingdom
  • London, United Kingdom
    • Moorfields Eye Hospital
  • Oxford
    • Headington, Oxford, United Kingdom, OX3 9DU
      • Oxford Eye Hospital
• United States
  • California
    • San Diego, California, United States, 92093-0946
      • Shiley Eye Institute - UC San Diego
    • San Francisco, California, United States, 94158
      • University of California, San Francisco
  • Florida
    • Miami, Florida, United States, 33136
      • University of Miami, Bascom Palmer Eye Institute
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Emory Eye Center
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • Wilmer Eye Institute, Johns Hopkins Hospital
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Center for Clinical Research Operations, Massachusetts Eye and Ear
  • Michigan
    • Ann Arbor, Michigan, United States, 48105
      • University of Michigan, Kellogg Eye Center
  • New York
    • New York, New York, United States, 10032
      • Columbia University
  • Texas
    • Dallas, Texas, United States, 75231
      • Retina Foundation of the Southwest
  • Wisconsin
    • Madison, Wisconsin, United States, 53705
      • University of Wisconsin - Madison

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 12 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Male or female, ≥ 18 years of age OR a minor (12 to < 18 years) with permission from a parent or legal guardian. The lower age limit for pediatric populations is subject to local regulatory and ethics committee requirements.
2. An adult willing to comply with the protocol, follow study instructions, attend study visits as required and willing and able to complete all study assessments. OR A minor able to complete all study assessments and comply with the protocol and has a parent or caregiver willing and able to follow study instructions, and attend study visits with the subject as required.
3. Clinical presentation consistent with RP with Usher syndrome type 2 or nonsyndromic form of RP (NSRP), based on ophthalmic, audiologic, and vestibular examinations.
4. A molecular diagnosis of homozygosity or compound heterozygosity for 1 or more pathogenic exon 13 mutations in the USH2A gene, based on genetic analysis at screening.
5. BCVA between ≥30 and ≤68 letters (approximate Snellen equivalent 20/250 - 20/50) in the treatment eye using the mean BCVA reading at screening. Subjects with a mean BCVA between >68 and ≤73 letters will be allowed with documented historic evidence of a BCVA equivalent decline of >5 letters in both eyes.
6. BCVA between ≥30 and ≤73 letters (approximate Snellen equivalent 20/250 - 20/40) in the contralateral eye (CE), using the mean BCVA reading at Screening.

7. A difference in mean BCVA readings at Screening between the TE and CE of

   ≤10 letters (based on ETDRS). BCVA differences between eyes that are greater than 10 letters may be allowed however, the Investigator should discuss the case with the Medical Monitor.

8. Stable BCVA in the TE and CE, defined as 2 separate BCVA measurements at Screening that fall within ≤ 5 letters for each respective eye.
9. A visible EZ layer on SD-OCT in the TE, as determined by the Investigator.
10. 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.
11. Reliable BCVA, perimetry, and other measurements in both eyes, as described in the Study Reference Manual and Imaging Manual and determined by the Investigator.
12. No visually significant ocular media opacities and adequate pupillary dilation to permit good quality retinal imaging in both eyes, 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 have monoallelic exon-13 mutations.
2. Presence of non-exon 13 USH2A pathogenic mutation(s) on both USH2A alleles in subjects who have biallelic exon 13 mutations.
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. Note: The confirmed presence of homozygous or compound heterozygous known disease-causing mutations in other genes involved in recessive retinal dystrophies (RD), or the confirmed presence of known disease-causing mutations in genes involved in dominant or X-linked retinal dystrophies is exclusionary.
4. Presence of any significant ocular (in either eye) 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). 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 study 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 either eye that resulted in significant vision loss, in the opinion of the Investigator.
9. 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 in either eye during the course of the study. For YAG laser treatment of a posterior capsular opacity, receipt within 1 month prior to Screening or planned procedure in either eye during the course of the study.
10. 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.
11. A history of glaucoma or an IOP greater than 21 mmHg in either eye that is not controlled with medication or surgery. IOP measurements between 21 and 24 mmHg may be allowed however, the Investigator should discuss the case with the Medical Monitor.
12. 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 course of the study.
13. Any prior treatment with genetic or stem-cell therapy for ocular or non-ocular disease.
14. History of malignancy within 2 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.
15. Known hypersensitivity to antisense oligonucleotides or any constituents of the injection.
16. Pregnant and breastfeeding subjects. Females of childbearing potential and males must comply with using highly effective methods of contraception as defined in the protocol. Women of non-childbearing potential may be included without the use of adequate birth control.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Sham Comparator: Sham-procedure; Sham-procedure (no experimental drug administered) on Day 1, Month 3 and every 6 months thereafter	Other: Sham-procedure; Sham-procedure (no experimental drug administered)
Experimental: Ultevursen 180/60 µg; 180 µg loading dose administered on Day 1, 60 µg maintenance dose administered at Month 3 and every 6 months thereafter	Drug: Ultevursen; RNA antisense oligonucleotide for intravitreal injection; Other Names: RNA antisense oligonucleotide for intravitreal injection
Experimental: Ultevursen 60/60 µg; 60 µg loading dose administered on Day 1, 60 µg maintenance dose administered at Month 3 and every 6 months thereafter	Drug: Ultevursen; RNA antisense oligonucleotide for intravitreal injection; Other Names: RNA antisense oligonucleotide for intravitreal injection

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mean change from baseline in BCVA	Mean change from baseline in best corrected visual acuity(BCVA) based on the Early Treatment Diabetic Retinopathy Study (ETDRS) chart	18 months of treatment versus sham-procedure

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Ocular and non-ocular adverse events (AEs)	Ocular and non-ocular adverse events (AEs)	27 months
Proportion of patients who maintain vision defined by BCVA loss less than 15 Letters (ETDRS)	Proportion of patients who maintain vision defined by BCVA loss less than 15 Letters based on ETDRS	27 months
Change from baseline in other analyses of BCVA	Change from baseline in other analyses of BCVA	27 months
Change from baseline in ellipsoid zone (EZ) area and width as imaged by spectral domain optical coherence tomography (SD-OCT)	Change from baseline in ellipsoid zone (EZ) area and width as imaged by spectral domain optical coherence tomography (SD-OCT)	27 months
Change from baseline in Low Luminance Visual Acuity (LLVA)	Change from baseline in Low Luminance Visual Acuity (LLVA)	27 months
Change from baseline in Microperimetry	Change from baseline in Microperimetry	27 months
Change from baseline in Full-field Stimulus Threshold (FST)	Change from baseline in Full-field Stimulus Threshold (FST)	27 months
Change from baseline in PRO measures	As assessed by the Veteran Affairs Low Vision Visual Functioning Questionnaire (VA LV VFQ-20), Patient Global Impressions of Severity (PGI-S) and Patient Global Impressions of Change (PGI-C)	27 months
Cmax of ultevursen in serum	Maximum concentration (Cmax) of ultevursen in serum	27 months

Collaborators and Investigators

• Sponsor: ProQR Therapeutics
• Investigators: Study Director: ProQR Medical Monitor, ProQR Therapeutics; Study Director: ProQR Clinical Trial Manager, ProQR Therapeutics

Study record dates

Study Major Dates

• Study Start (Actual): December 8, 2021
• Primary Completion (Anticipated): December 1, 2024
• Study Completion (Anticipated): December 1, 2024

Study Registration Dates

• First Submitted: November 23, 2021
• First Submitted That Met QC Criteria: December 1, 2021
• First Posted (Actual): December 15, 2021

Study Record Updates

• Last Update Posted (Actual): September 16, 2022
• Last Update Submitted That Met QC Criteria: September 15, 2022
• Last Verified: September 1, 2022

More Information

Terms related to this study

• Keywords: RP; Retinitis Pigmentosa; Intravitreal Injection; Usher Syndrome; USH2A; exon 13; RNA therapies; antisense oligonucleotide; exon skipping; IVT; mutations in exon 13 of the USH2A gene; NSRP; Non-Syndromic RP; Inherited Retinal Disorders; Sirius; ultevursen
• Additional Relevant MeSH Terms: Pathologic Processes; Nervous System Diseases; Neurologic Manifestations; Congenital Abnormalities; Retinal Degeneration; Otorhinolaryngologic Diseases; Ear Diseases; Retinal Dystrophies; Sensation Disorders; Abnormalities, Multiple; Hearing Disorders; Deaf-Blind Disorders; Hearing Loss, Sensorineural; Blindness; Hearing Loss; Deafness; Disease; Retinal Diseases; Retinitis; Retinitis Pigmentosa; Eye Diseases; Usher Syndromes; Genetic Diseases, Inborn; Vision Disorders; Eye Diseases, Hereditary; Eye Abnormalities
• Other Study ID Numbers: PQ-421a-003; 2021-002729-74 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No