Evaluation of Safety, Tolerability, and Pharmacokinetics of Single Ascending Doses of STK-002 in Autosomal Dominant Optic Atrophy Patients

The primary objective of this study is to evaluate the **safety** and **tolerability** of single ascending doses of STK-002 in patients with **Autosomal Dominant Optic Atrophy** (ADOA). Additionally, the study aims to determine the exposure in serum following single intravitreal doses of STK-002. These objectives are clinically relevant as they assess the potential risks and pharmacokinetics of STK-002, which is crucial for understanding its therapeutic viability and ensuring patient safety.

Secondary objectives include evaluating changes in visual function and ocular structure following single doses of STK-002, as well as assessing the effect of these doses on the quality of life in patients with ADOA. These objectives are important for determining the broader impact of STK-002 on patient outcomes beyond safety and pharmacokinetics.

The clinical trial involves a total of **23 participants** diagnosed with **Autosomal Dominant Optic Atrophy (ADOA)**. The study population includes both male and female subjects, with an age range of 6 to 54 years. Participants were selected based on specific inclusion criteria, including a confirmed heterozygous OPA1 gene variant and a Best Corrected Visual Acuity (BCVA) ETDRS letter score within a defined range. The trial encompasses a vulnerable population, indicating careful consideration of ethical standards. Participants' general health status and lifestyle factors such as diet and physical activity were not specified by the sponsor. The selection process ensures a representative sample of individuals affected by ADOA, facilitating the evaluation of the safety and tolerability of the investigational treatment.

The clinical trial is designed to evaluate the **safety** and **tolerability** of single ascending doses of STK-002 in patients diagnosed with **Autosomal Dominant Optic Atrophy** (ADOA). This Phase I trial will also assess the exposure of STK-002 in serum following single intravitreal doses. The study is structured as an open-label trial, which means that both the researchers and participants will be aware of the treatment being administered. The trial is expected to commence recruitment on March 15, 2024, and conclude by December 8, 2026.

Participants will undergo a series of study visits, beginning with a screening visit to confirm eligibility based on specific inclusion criteria, such as age and a confirmed heterozygous OPA1 gene variant. The trial will include multiple follow-up visits to monitor safety variables and pharmacokinetic parameters. Secondary endpoints will be evaluated through assessments such as optical coherence tomography (OCT) for retinal nerve fiber layer thickness, best-corrected visual acuity (BCVA), and quality of life questionnaires. The end-of-study visit will mark the completion of the participant's involvement in the trial.

The expected duration of participant involvement will vary depending on the cohort assignment and the dosing schedule. Participants may be withdrawn from the study early if they experience adverse events that compromise their safety or if they fail to comply with the study protocol. The trial will adhere to rigorous ethical standards and regulatory requirements to ensure the integrity of the data collected and the safety of all participants.

The clinical trial involves the administration of the experimental medication **STK-002**, which is a **solution for injection**. The active substance in STK-002 is an **18-mer antisense oligonucleotide complementary to OPA1 pre-mRNA**, originating from nucleic acid. This investigational product is designed for **intravitreal use** and is administered as a single ascending dose to evaluate its safety, tolerability, and exposure in patients with Autosomal Dominant Optic Atrophy (ADOA). The pharmaceutical form of STK-002 is a solution for injection, and it is not a pediatric formulation. The medication is of chemical origin and is developed by Stoke Therapeutics, Inc.

In this study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are mentioned. The focus is solely on the administration of STK-002. The trial aims to assess the exposure of the drug in serum following the intravitreal administration. Participant compliance and dosing schedules are monitored to ensure the accurate evaluation of the investigational product's effects. The study does not specify a maximum daily dose, total dose, or treatment period, indicating that the primary objective is to explore the safety and pharmacokinetics of the single doses administered.

Efficacy in this clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoints focus on safety variables and the exposure of STK-002 in serum, which will be determined using pharmacokinetic (PK) parameters. Secondary endpoints include several measures of visual function and quality of life. These include the thickness of the peripapillary retinal nerve fiber layer (RNFL) and macular ganglion cell layer (GCL) as assessed by optical coherence tomography (OCT), best-corrected visual acuity (BCVA) using Early Treatment Diabetic Retinopathy Study (ETDRS) optotypes, and contrast sensitivity evaluated by low contrast BCVA at 25%, 5%, and 2.5% contrast levels. Additionally, visual field assessments will be conducted using automated, static perimetry with the 10-2 and 24-2 Swedish Interactive Threshold Algorithm (SITA) FAST. The electrical activity of the retina will be measured by phototopic negative response (PhNR) electroretinography (ERG), if available. Continuous text reading acuity will be assessed using MNREAD Acuity Charts. Quality of life will be evaluated through scores on the National Eye Institute Visual Function Questionnaire-25 (NEI-VFQ-25), Impact of Vision Impairment for Children (IVI-C), and the European Quality of Life-5 Dimensions (EQ-5D)/EQ-5D-Y questionnaire. These assessments will provide comprehensive data on the efficacy of STK-002 in patients with **Autosomal Dominant Optic Atrophy**.