Evaluation of Ultevursen Efficacy, Safety, and Tolerability in Retinitis Pigmentosa Patients with USH2A Exon 13 Mutations: A Double-Masked, Randomized, Sham-Controlled Trial

Trial ID: 2024-515199-10-01
Protocol: SB-421a-006
Sponsor: Laboratoires Thea

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Diseases & Conditions

Retinitis pigmentosa

Objectives

The primary objective of this study is to evaluate the **efficacy** of ultevursen after 24 months of treatment in subjects with **Retinitis Pigmentosa** due to mutations in exon 13 of the USH2A gene. This is clinically relevant as it aims to determine the therapeutic potential of ultevursen in slowing or halting the progression of this degenerative retinal disease, which can lead to significant visual impairment.

Secondary objectives include:

To evaluate the efficacy of other endpoints and/or timepoints, providing a comprehensive understanding of ultevursen's impact over different measures and durations.
To evaluate the **safety** and **tolerability** of ultevursen, ensuring that the treatment is not only effective but also safe for long-term use.
To evaluate the systemic exposure of ultevursen, which is crucial for understanding the pharmacokinetics and potential systemic effects of the drug.

Participants

The clinical trial involves a total of **50 participants** diagnosed with **Retinitis Pigmentosa**. The study population includes both male and female subjects, with an age range spanning from 12 to adults aged 18 years and older. Participants were selected based on specific criteria, including the ability to provide informed consent or assent, and the presence of a molecular diagnosis of biallelic disease-causing variants in the USH2A gene. The trial includes individuals with both Usher syndrome type 2 and non-syndromic Retinitis Pigmentosa, as determined by ophthalmic, audiologic, or vestibular examinations. Participants are required to have a baseline visual acuity of at least 55 letters based on the ETDRS scale and must not have visually significant ocular media opacities. The study population is characterized by a commitment to comply with the study protocol, including attending study visits and completing all assessments. Both male and female subjects of childbearing potential are required to use highly effective contraception methods. The trial does not exclude vulnerable populations, ensuring a comprehensive evaluation of the treatment's efficacy over a 24-month period.

Plans and Procedures

The clinical trial is designed as a **randomized**, **double-masked**, **sham-controlled** study to evaluate the efficacy, safety, and tolerability of **ultevursen** in subjects with **Retinitis Pigmentosa** due to mutations in exon 13 of the USH2A gene. The trial will span a duration of 24 months, with the primary objective being to assess the efficacy of the treatment over this period. Participants will be randomly assigned to receive either the active treatment or a sham procedure that mimics the injection without actual penetration of the globe. The study will involve multiple visits, starting with an inclusion (screening) visit to determine eligibility based on specific criteria, including age, visual acuity, and genetic diagnosis.

Following the screening, eligible participants will undergo baseline assessments before the initiation of treatment. The trial will include regular follow-up visits at specified intervals to monitor the participants' response to the treatment and to assess any adverse events. These visits will involve comprehensive ophthalmic evaluations, including measurements of retinal sensitivity and visual acuity, as well as safety assessments. The end-of-study visit will occur at the conclusion of the 24-month treatment period, where final evaluations will be conducted to determine the overall outcomes of the trial.

Participant involvement is expected to last for the entire 24-month duration of the study, provided they meet all ongoing eligibility criteria and do not experience any conditions that necessitate early termination. Conditions that may lead to early withdrawal from the study include significant adverse events, non-compliance with study procedures, or any other medical reasons deemed necessary by the investigator. The trial aims to provide valuable data on the potential benefits and risks associated with ultevursen for individuals affected by this genetic form of **Retinitis Pigmentosa**.

Treatment

The clinical trial involves the administration of **ultevursen**, an experimental medication, in the form of a **solution for injection**. Ultevursen is an antisense oligonucleotide targeting exon 13 in the USH2A gene, specifically designed for the treatment of **retinitis pigmentosa** due to mutations in this exon. The pharmaceutical form is a solution for injection, and the route of administration is intravitreal use. Two dosing regimens are employed in the study: a maximum daily dose of 180 micrograms administered over a treatment period of 1 month, and a second regimen with a maximum daily dose of 60 micrograms administered over a treatment period of 18 months. The total maximum dose for both regimens is 180 micrograms. The medication is provided by Laboratoires Thea and is identified by the sponsor product code QR-421a.

In addition to the experimental treatment, a sham procedure is utilized as a comparator in the study. Participants in the sham group undergo a procedure that closely mimics the active injection but without penetration of the globe. This approach is designed to maintain the double-masked nature of the trial, ensuring that neither the participants nor the investigators are aware of the treatment allocation. The sham procedure does not involve any active pharmaceutical ingredient and serves as a control to evaluate the efficacy and safety of ultevursen.

Efficacy

The efficacy of **Ultevursen** in the treatment of **Retinitis Pigmentosa** due to mutations in exon 13 of the USH2A gene will be assessed through a series of primary and secondary endpoints. The primary endpoint is the annualized percent change from baseline in ellipsoid zone (EZ) width as measured by spectral-domain optical coherence tomography (SD-OCT) up to Month 24. Secondary endpoints include changes in retinal sensitivity measured by static perimetry (SP) and microperimetry (MP) with topographic analysis (Hill of Vision [HoV]), changes from baseline in low luminance visual acuity (LLVA) and best-corrected visual acuity (BCVA) using the Early Treatment Diabetic Retinopathy Study (ETDRS) chart, and percent changes from baseline in EZ area and width by SD-OCT. These endpoints will be evaluated at Months 12 and 24.

Additional efficacy assessments involve changes from baseline in virtual visual maze performance score using the Mobility Standardized Test in Virtual Reality (MOSTVR), changes in dark-adapted full-field stimulus threshold (FST) testing, and changes in each domain of the Michigan Retinal Degeneration Questionnaire (MRDQ) and Michigan Vision-Related Anxiety Questionnaire (MVAQ) scores for subjects aged 13 years and older. The study will also monitor the frequency and severity of ocular and non-ocular adverse events, the incidence of anti-drug antibodies against ultevursen, and systemic serum concentration of ultevursen. These assessments will be conducted at specified intervals throughout the trial duration to ensure comprehensive evaluation of the treatment's efficacy and safety.

Inclusion and Exclusion Criteria

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Inclusion Criteria

An adult (≥18 years) willing and able to provide informed consent for participation prior to performing any study related procedures OR A minor (12 to <18 years) able to provide age-appropriate assent for study participation with a parent(s) or legal guardian(s) willing and able to provide written permission for the subject’s participation prior to performing any study related procedures
Adult willing to comply with the protocol, follow the study instructions, attend study visits as requested, and accept and be able to undergo all study assessments, in the opinion of the investigator.
Both eyes present a clinical picture compatible with retinitis pigmentosa (RP) involving a type 2 Usher syndrome or non-syndromic RP according to ophthalmological, audiological, or vestibular examinations. During selection, the investigator will make a clinical diagnosis of 'type 2a Usher syndrome,' defined as RP with congenital hearing loss, or 'non-syndromic RP,' defined as RP without congenital hearing loss.
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.
Clearly visible and measurable SD-OCT horizontal EZ width of ≥2.2 mm in both eyes based on the assessment of the CRC
MCVA ≥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.
Impairment of VF as assessed by SP with a mean sensitivity >4 decibels (dB) and <25 dB measured by a V target size in the TE at screening (see footnote o in Table 1-1 for more details on subjects who require N-acetylcysteine [NAC] washout).
Mean sensitivity >2 dB as determined by MP in the TE at screening (see footnote o in Table 1-1 for more details on subjects who require NAC washout).
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.
During the screening period, the difference of BCVA letters (based on ETDRS) from 2 measurements taken separately will need to be within 10 letters. After 3 attempts of the BCVA measurement, if a reliable baseline cannot be obtained, the subject is ineligible.
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. For purposes of determining symmetry, the mean BCVA for each eye will be calculated using all BCVA measures obtained during the screening period.
At screening, reliable measurements in MP and SP as described in the Study Reference Manual.
No visually significant ocular media opacities and adequate pupillary dilation to permit good quality retinal visibility or imaging in either eye, as assessed by the Investigator.
Non-pregnant and non-breastfeeding subjects. Women of childbearing potential (WOCBP) and fertile males must comply with using highly effective methods of contraception (see Section 14.2 for definitions of WOCBP and fertile males and details on highly effective contraception methods). Women of non-childbearing potential may be included without the use of adequate birth control, provided they meet the entry criteria for the study.

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Exclusion Criteria

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.
Presence of additional non-exon 13 USH2A pathogenic mutation(s) on both USH2A alleles in subjects who have biallelic exon 13 mutations.
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.
Any contraindication to IVT injection according to the Investigator’s clinical judgment and the American Academy of Ophthalmology (Avery 2014). This includes any active or suspected intraocular inflammation or active or suspected ocular or periocular infection in either eye.
At screening, the EZ horizontal width is outside the field of the SDOCT scan based on the assessment of the CRC
Presence of any significant ocular or non-ocular disease/disorder (including medication and laboratory test abnormalities) which, in the opinion of the Investigator, 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.
Presence of unstable concurrent cystoid macular edema (CME), or subject started on (or changed dose of) any medication for CME 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.
Any intraocular surgery within 3 months of study entry or any planned intraocular or peri-ocular surgery during the study. Subjects may be eligible after 3 months post-surgery as long as they have fully recovered, in the opinion of the Investigator.
Receipt of any IVT injection prior to study entry.
History or presence of ocular herpetic disease (including herpes simplex virus, varicella zoster or cytomegalovirus) in either eye.
Presence of any of the following lens opacities in the TE based on the Age-Related Eye Disease Study (AREDS) lens grading scale: 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. Subjects should not be entered into the study if there is likelihood they will require cataract surgery in the TE during the study.
History of amblyopia in the TE that has resulted in vision loss, in the opinion of the Investigator.
Presence of significant keratopathy or any other media or corneal opacity that would cause scattering of light or alter visual function, especially in low luminance conditions in the TE.
A history of glaucoma or an IOP greater than 24 mmHg in the TE that is not controlled with medication or surgery at the time of informed consent.
Use of any investigational drug or device within 3 months or 5 halflives of Day 1, whichever is longer, or plans to participate in another study of a drug or device during the study. However, for those subjects in NAC trials or taking over-the-counter supplements containing NAC at screening, SP and MP eligibility must be reverified at baseline following a minimum of 3 months of NAC washout prior to randomization (refer to Table 1-1)
Any prior receipt of genetic or stem-cell therapy for ocular or non-ocular disease.
Known hypersensitivity to antisense oligonucleotides or any constituents of the injection.
Current chronic treatment or treatment within the past 12 months with therapies known to influence the immune system (including but not limited to steroid implants, chronic systemic steroids, cytostatics, interferons, tumor necrosis factor (TNF)-binding proteins, drugs acting on immunophilins, or antibodies with known impact on the immune system). Subjects who have been treated on a short course of systemic steroids within the past 12 months or who require the use of topical steroids may be considered for inclusion
Current use of medications known to be toxic to the lens, retina, or optic nerve (e.g., deferoxamine, chloroquine/hydroxychloroquine [Plaquenil®], tamoxifen, phenothiazines, ethambutol, digoxin, pentosan polysulfate sodium, and amiodarone).
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.

Trial Status by Country

Country	Status	Start of Recruitment	Planned Patients
Belgium	Not Recruiting	21 Aug 2025	1
Denmark	Not Recruiting	21 Aug 2025	1
France	Not Recruiting	21 Aug 2025	10
Germany	Not Recruiting	21 Aug 2025	4
Italy	Not Recruiting	21 Aug 2025	3
The Netherlands	Not Recruiting	21 Aug 2025	—
Netherlands	—	—	12