Clinical trial NCT05158296: 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)
Official title: 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)
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
PHASE3
Conditions: Retinitis Pigmentosa
Usher Syndrome Type 2
Deaf Blind
Retinal Disease
Eye Diseases
Eye Diseases, Hereditary
Eye Disorders Congenital
Vision Disorders
Keywords: Retinitis Pigmentosa
USH2A
RP
exon 13
RNA therapies
antisense oligonucleotide
exon skipping
Sirius
IVT
mutations in exon 13 of the USH2A gene
NSRP
Non-Syndromic RP
Inherited Retinal Disorders
Usher Syndrome
Intravitreal Injection
ultevursen
Lead sponsor: Laboratoires Thea
Sponsor class: INDUSTRY
Collaborators: name: Sepul Bio
First posted: 2021-12-15
Enrollment: 7
Sex: ALL
Minimum age (years): 12
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Double-masked, randomized, controlled, multiple-dose study. Subjects will be randomized to one of three treatment groups:

1. Group 1: 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)
2. Group 2: 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; n = 27)
3. Group 3: Sham-procedure (administered on Day 1, Month 3 and every 6 months thereafter; n = 27)
Primary purpose: TREATMENT

Brief summary: 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.

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

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

Eligibility criteria: 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.

Primary outcomes:
measure: Mean Change From Baseline in Best Corrected Visual Acuity (BCVA)
timeFrame: 18 months of treatment versus sham-procedure
Secondary outcomes:
measure: Proportion of Patients Who Maintain Vision Defined by BCVA Loss Less Than 15 Letters (ETDRS)
timeFrame: 27 months
measure: Change From Baseline in Other Analyses of Best Corrected Visual Acuity (BCVA)
timeFrame: 27 months
measure: Change From Baseline in Ellipsoid Zone (EZ) Area and Width as Imaged by Spectral Domain Optical Coherence Tomography (SD-OCT)
timeFrame: 27 months
measure: Change From Baseline in Low Luminance Visual Acuity (LLVA)
timeFrame: 27 months
measure: Change From Baseline in Microperimetry
timeFrame: 27 months
measure: Change From Baseline in Full-field Stimulus Threshold (FST)
timeFrame: 27 months
measure: Change From Baseline in PRO Measures
timeFrame: 27 months
measure: Ocular and Non-ocular Adverse Events (AEs)
timeFrame: 27 months
measure: Cmax of Ultevursen in Serum
timeFrame: 27 months
Other outcomes:
Locations:
city: San Diego
country: United States
facility: Shiley Eye Institute - UC San Diego
state: California
city: San Francisco
country: United States
facility: University of California, San Francisco
state: California
city: Miami
country: United States
facility: University of Miami, Bascom Palmer Eye Institute
state: Florida
city: Atlanta
country: United States
facility: Emory Eye Center
state: Georgia
city: Baltimore
country: United States
facility: Wilmer Eye Institute, Johns Hopkins Hospital
state: Maryland
city: Boston
country: United States
facility: Center for Clinical Research Operations, Massachusetts Eye and Ear
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan, Kellogg Eye Center
state: Michigan
city: New York
country: United States
facility: Columbia University
state: New York
city: Dallas
country: United States
facility: Retina Foundation of the Southwest
state: Texas
city: Madison
country: United States
facility: University of Wisconsin - Madison
state: Wisconsin
city: Tuebingen
country: Germany
facility: Universitaetsklinikum Tuebingen Department für Augenheilkunde
city: Nijmegen
country: Netherlands
facility: RadboudUMC
city: Rotterdam
country: Netherlands
facility: Het Oogziekenhuis Rotterdam
city: Headington
country: United Kingdom
facility: Oxford Eye Hospital
state: Oxford
city: London
country: United Kingdom
facility: Moorfields Eye Hospital
Study officials:
affiliation: Sepul Bio
name: Sepul Bio Medical Monitor
role: STUDY_DIRECTOR
affiliation: Sepul Bio
name: Sepul Bio Clinical Operations Director
role: STUDY_DIRECTOR
References: