Evaluation of the Safety and Efficacy of Subretinal CPK850 Gene Therapy in Patients with RLBP1-Associated Retinitis Pigmentosa

Trial ID: 2023-508688-54-00
Protocol: CCPK850X2202
Sponsor: Novartis Pharma AG

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Diseases & Conditions

Retinitis pigmentosa

Objectives

The primary objective of this study is to evaluate the **ocular** and systemic safety of a single dose of CPK850 in patients with retinitis pigmentosa caused by biallelic mutations in the RLBP1 gene. This includes assessing ophthalmic safety parameters such as best corrected visual acuity (BCVA), intraocular pressure (IOP), slit lamp examination (biomicroscopy), dilated fundus examination, optical coherence tomography (OCT), and color fundus photography (CFP) parameters. Systemic safety parameters include adverse events (AEs), blood chemistry, hematology, urinalysis, and vital signs. Additionally, the study aims to evaluate the efficacy of CPK850 by assessing the recovery of the rod system in treated eyes compared to pre-treatment assessments, focusing on dark adaptation (DA) recovery, pre-bleach DA values, bleaching effect, and dark adaptation kinetics.

Secondary objectives include evaluating the recovery of the cone system and rod system in eyes treated with CPK850 compared to pre-treatment assessments and untreated eyes. The study also aims to assess changes from baseline in measures of visual function, electrical rod and cone system function, and navigation skills in treated eyes. Furthermore, the effects of CPK850 on activities of daily living compared to pre-treatment assessments will be evaluated. These secondary objectives are crucial for understanding the broader impact of CPK850 on visual and functional outcomes in patients with retinitis pigmentosa.

Participants

The clinical trial involves **participants** diagnosed with retinitis pigmentosa caused by biallelic mutations in the RLBP1 gene. The study population includes both male and female subjects aged between 18 and 70 years. Participants are required to have a clinical diagnosis of progressive retinitis pigmentosa phenotypes such as Bothnia dystrophy or Newfoundland rod-cone dystrophy, confirmed through molecular genetics testing. The trial population was selected based on specific ocular and systemic health criteria, including clear ocular media and adequate pupil dilation, as well as a body mass index (BMI) of less than 40 kg/m². Participants must weigh at least 40 kg and have a visual acuity in the study eye of no better than 60 ETDRS letters. The trial includes individuals with visible photoreceptor and retinal pigment epithelium layers on standard optical coherence tomography (OCT) scans. The sponsor has not provided information regarding the total number of participants. The study considers lifestyle factors such as the ability to undergo surgical procedures and the presence of a dark adaptation bleaching effect in the study eye. The trial includes a vulnerable population, ensuring comprehensive safety and efficacy evaluations of the investigational treatment.

Plans and Procedures

The clinical trial is designed as an **open-label**, first-in-human, single ascending dose study to evaluate the safety, tolerability, and efficacy of subretinal administration of CPK850 gene therapy in patients with **retinitis pigmentosa** caused by biallelic mutations in the RLBP1 gene. The trial is categorized as an integrated phase 1-2 trial, with an estimated duration from April 16, 2018, to May 11, 2026. The study involves a series of visits, beginning with a screening visit to confirm eligibility based on specific inclusion criteria, such as age, ocular health, and genetic diagnosis. Participants will undergo a comprehensive ophthalmic and systemic safety assessment, including best corrected visual acuity, intraocular pressure, and optical coherence tomography, among others.

Following the screening, eligible participants will receive a single dose of CPK850 via subretinal injection. The primary endpoints include the number of participants experiencing adverse events and the number of responders in dark adaptation. Secondary endpoints focus on improvements in visual function and retinal activity. Participants will be monitored through follow-up visits to assess safety and efficacy outcomes, with specific attention to dark adaptation recovery and visual acuity changes. The end-of-study visit will conclude the trial, summarizing the overall safety and efficacy findings.

Participant involvement is expected to last up to one year post-treatment, with conditions for early termination including significant adverse events or withdrawal of consent. The trial aims to provide valuable insights into the potential therapeutic benefits of CPK850 for individuals with this genetic form of retinitis pigmentosa, contributing to the understanding of gene therapy applications in ophthalmology.

Treatment

The clinical trial involves the administration of **CPK850**, an experimental gene therapy product developed by Novartis Pharma AG. **CPK850** is formulated as a **solution for injection** and is designed for subretinal administration. The active substance in **CPK850** is a nucleic acid-based vector expressing the hRLBP1 gene from a truncated region of the endogenous hRLBP1. This vector is a replication-deficient recombinant adeno-associated viral (AAV) vector. The therapy is administered as a single ascending dose to evaluate its safety, tolerability, and efficacy in patients with retinitis pigmentosa caused by mutations in the RLBP1 gene. The administration route is specifically subretinal, targeting the affected area directly.

In this study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are utilized. The focus is solely on the effects of the **CPK850** gene therapy. The trial is designed to monitor both ocular and systemic safety parameters, including best corrected visual acuity (BCVA), intraocular pressure (IOP), and other ophthalmic assessments, as well as systemic safety through adverse events, blood chemistry, hematology, urinalysis, and vital signs. Participant compliance is monitored through these safety assessments and the evaluation of efficacy parameters, such as the recovery of the rod system in treated eyes compared to pre-treatment assessments.

Efficacy

The efficacy of the clinical trial will be assessed by evaluating the recovery of the rod system in eyes treated with CPK850, a gene therapy for **retinitis pigmentosa** caused by mutations in the RLBP1 gene. The primary efficacy endpoint includes the number of responders in dark adaptation, where a patient is considered a responder if sensitivity recovery values at 1-hour post-bleach are observed to be outside of the patient's prediction interval at two or more consecutive post-treatment visits within one year after treatment. Secondary efficacy endpoints will include the number of patients with recovery of the cone system and improvement in rod function in the treated eye compared to the untreated eye.

Additional secondary endpoints involve changes from screening or baseline in various parameters such as visual field perimetry mean deviation, total contrast sensitivity score, light-adapted microperimetry sensitivity, reading speed, local electrical activity of the retina, eye dominance, mobility test scores, and composite scores from the National Eye Institute - Visual Function Questionnaire 25 (NEI-VFQ 25) and the low luminance questionnaire (LLQ). The Functional Vision Questionnaire (FVQ) responses and changes in the electrical activity of the retina will also be assessed. These efficacy parameters will be measured and collected at specified timepoints throughout the trial, using validated scales and patient-reported outcomes where applicable.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Written informed consent must be obtained before any assessment is performed.
Male and female patients aged 18 to 70 years. All female patients must have negative pregnancy test results at the screening visits and just prior to the treatment day.
The patients must have sufficiently clear ocular media and adequate pupil dilation to permit fundus photographs of adequate clarity and performance of vitrectomy and subretinal injection.
Patients must meet surgical requirements. In addition, patients must weigh at least 40 kg to participate in the study, and must have a body mass index (BMI) <40 kg/m2. BMI = Body weight (kg) / [Height (m)]2.
The visual acuity in the study eye at the screening 1 visit should be no better than 60 early treatment diabetic retinopathy study (ETDRS) letters. In Cohort 1, patients with visual acuity from 35 ETDRS letters to Hand Motion visual acuity will be included. For Cohorts 2 and beyond, patients with visual acuity of 60 ETDRS letters to Hand Motion visual acuity will be enrolled. Consideration for inclusion in Cohorts 1 and 2 only may be given to patients with visual acuity as low as Light Perception at the screening 1 visit, if they meet all other inclusion/exclusion criteria and at the agreement of the sponsor and principal investigators.
Clinical diagnosis of Bothnia dystrophy, Newfoundland rod-cone dystrophy or other progressive retinitis pigmentosa phenotype with biallelic mutations in the RLBP1 gene verified by Clinical Laboratory Improvement Amendments (CLIA), Good Laboratory Practices (GLP) or equivalent molecular genetics testing.
Visible photoreceptor (outer nuclear) and retinal pigment epithelium (RPE) layers on standard OCT scan in the study eye at the screening 1 visit as confirmed by the Central Reading Center.
Dark adaptation bleaching effect in the study eye at short wavelength stimulus of > 1.0 log unit at 2 of the 3 baseline measures obtained prior to treatment.

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Exclusion Criteria

Unable or unwilling to meet requirements of the study
History of hypersensitivity to the study drug or to drugs of similar classes or to any of the medications required in the perioperative period.
Pre-existing eye conditions that would preclude the planned surgery or interfere with the interpretation of study endpoints; for example: glaucoma (IOP ≥25 mm Hg despite treatment with anti-glaucoma medication or low tension glaucoma), corneal or significant lenticular opacities, retinal vascular occlusion, retinal detachment, macular hole, or choroidal neovascularization of any cause.
Any active infection or ocular disease involving ocular adnexa including infectious conjunctivitis, keratitis, scleritis, endophthalmitis, as well as idiopathic or autoimmune-associated uveitis in either eye.
Any contraindication to the planned surgery or anesthesia as determined by the treating physician (surgeon, anesthesiologist, primary care physician or designee). Use of systemic anticoagulant therapies during the study, such as warfarin, heparin or similar are to be evaluated by the treating physician as potential exclusions. The use of aspirin is not usually an exclusion criterion unless indicated by the treating physician. Abnormal vital signs and/or Electrocardiograms (ECGs) that suggest potential contraindications for planned study anesthesia are exclusions.
Known history of or current clinically significant arrhythmias, myocardial infarction, coronary bypass surgery, or any percutaneous coronary intervention (PCI) within 6 months prior to screening or patients with heart failure New York Heart Association (NYHA) class IIIV at the discretion of the treating physician or cardiologist.
Cerebrovascular accident (stroke) within the 12 months prior to screening at the discretion of the treating physician.
Complicating systemic diseases or clinically significant abnormal laboratory values. Complicating systemic diseases would include those in which the disease itself, or the treatment for the disease, can alter ocular function. Examples are malignancies whose treatment could affect central nervous system function (for example radiation treatment of the orbit; leukemia with central nervous system (CNS)/optic nerve involvement). Also patients with immunocompromising diseases would be excluded since they would have susceptibility to opportunistic infections.
Women who are pregnant or nursing (lactating), as well as male and female patients of childbearing potential that are unwilling to use contraception as per study requirements.